Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions

ABSTRACT

The inventions disclosed herein relate to the discovery of the use of compounds having the formula shown below 
                         
and certain subgenera or species thereof, as flavor or taste modifiers, particularly, savory (“umami”) taste modifiers, savory flavoring agents and savory flavor enhancers in foods, beverages, and other comestible compositions.

RELATED APPLICATIONS

This application claims the priority of U.S. provisional patentapplication Ser. No. 60/650,029 filed on Feb. 4, 2005, the entiredisclosure of which is hereby incorporated herein by this reference, forall purposes.

FIELD OF THE INVENTION

The present invention relates to the discovery of flavor or tastemodifiers, such as a flavoring or flavoring agents and flavor or tasteenhancers, more particularly, savory (“umami”) taste modifiers, savoryflavoring agents and savory flavor enhancers, for foods, beverages, andother comestible compositions.

BACKGROUND OF THE INVENTION

For centuries, various natural and unnatural compositions and/orcompounds have been added to foods, beverages, and/or comestible(edible) compositions to improve their taste. Although it has long beenknown that there are only a few basic types of “tastes” (sweet, sour,bitter, salty, and “umami”/savory), the biological and biochemical basisof taste perception was poorly understood, and most taste improving ortaste modifying agents have been discovered largely by simple trial anderror processes.

For example, one of the five known basic tastes is the “savory” or“umami” flavor of monosodium glutamate (“MSG”), which is now commonlyadded to many food and beverage compositions to desirably improve their“savory” flavor. MSG is known to produce adverse reactions in somepeople, but very little progress has been made in identifying artificialsubstitutes for MSG. It is known that a few naturally occurringmaterials can increase or enhance the effectiveness of MSG as a savoryflavoring agent, so that less MSG is needed for a given flavoringapplication. For example the naturally occurring nucleotide compoundsinosine monophosphate (IMP) or guanosine monophosphate (GMP) are knownto have a synergistic and/or multiplier effect on the savory taste ofMSG. Nevertheless, IMP and GMP are difficult and expensive to isolateand purify from natural sources, or synthesize, and hence have limitedpractical application to many commercial needs in food compositions.Less expensive compounds that would provide and/or replace the flavor ofMSG itself, or multiply the effectiveness of any MSG that is present soas to replace the need for the addition of IMP or GMP additives could beof very high value, especially if the compounds could be used atextremely low concentrations, so as to minimize costs and any possiblehealth risks.

In recent years substantial progress has been made in biotechnology ingeneral, and in better understanding the underlying biological andbiochemical phenomena of taste perception. For example, taste receptorproteins have been recently identified in mammals which are involved intaste perception. Particularly, two different families of G proteincoupled receptors believed to be involved in taste perception, T2Rs andT1Rs, have been identified. (See, e.g., Nelson, et al., Cell (2001)106(3):381-390; Adler, et al., Cell (2000) 100(6):693-702;Chandrashekar, et al., Cell (2000) 100:703-711; Matsunami, et al.,Number (2000) 404:601-604; Li, et al., Proc. Natl. Acad. Sci. USA (2002)99:4962-4966; Montmayeur, et al., Nature Neuroscience (2001)4(S):492-498: U.S. Pat. No. 6,462,148; and PCT publications WO 02/06254,WO 00/63166 art, WO 02/064631, and WO 03/001876, and U.S. Patentpublication US 2003-0232407 A1). The entire disclosures of the articles,patent applications, and issued patents cited immediately above arehereby incorporated herein by reference, for all purposes, includingtheir disclosures of the identities and structures of T2Rs and T1Rsmammalian taste receptor proteins and methods for artificiallyexpressing those receptors in cell lines and using the resulting celllines for screening compounds as potential “savory” flavoring agents.

Whereas the T2R family includes a family of over 25 genes that areinvolved in bitter taste perception, the T1Rs only includes threemembers, T1R1, T1R2 and T1R3. (See Li, et al., Proc. Natl. Acad. Sci.USA (2002) 99:4962-4966.) Recently it was disclosed in WO 02/064631and/or WO 03/001876 that certain T1R members, when co-expressed insuitable mammalian cell lines, assemble to form functional tastereceptors. Particularly it was found that co-expression of T1R1 and T1R3in a suitable host cell results in a functional T1R1/T1R3 savory(“umami”) taste receptor that responds to savory taste stimuli,including monosodium glutamate. (See Li, et al. (Id.). The referencescited above also disclosed assays and/or high throughput screens thatmeasure T1R1/T1R3 or T1R2/T1R3 receptor activity by fluorometric imagingin the presence of the target compounds.

Very recently, certain U.S. and international patent applications havebeen filed by some of the current Applicants that disclosed the use ofcertain amide compounds as umami and/or sweet tastants, and/orsynergistic enhancers of the “Umami” taste of MSG, and/or the sweettaste of a variety of natural and artificial sweeteners. See, forexample, U.S. Provisional Patent Application Ser. No. 60/494,071 filedAug. 6, 2003, U.S. Provisional Patent Application Ser. No. 60/552,064filed Mar. 9, 2004, U.S. Utility patent application Ser. No. 10/913,303,filed Aug. 6, 2004 and published as U.S. Patent Publication Serial No.US-2005-0084506-A1 on Apr. 21, 2005; and PCT Patent Application SerialNo. PCT/US04/25419 filed Aug. 6, 2004 and published as PCT PublicationWO 2005/041684 on May 12, 2005, and PCT Publication WO 2005/015158published on Feb. 17, 2005. The entire disclosures of the patentapplications cited immediately above are hereby incorporated herein bythis reference, for all purposes, including their disclosures of theidentities and structures of amide compounds that can serve as potential“savory” or sweet flavoring agents or enhancers. Nevertheless, there isa continuing need for new and improved taste enhancing compounds.

We employed the above-described assays and/or high throughput screeningmethods to identify from a very large number of initial compounds a veryfew linked heteroaryl “lead” compounds that modulate the activity ofT1R1/T1R3 “savory” taste receptors, then embarked on a long, complex anditerative process of investigation, evaluation and revision, andchemical structural optimization, so as to arrive at the variousinventions described below.

SUMMARY OF THE INVENTION

The invention has many aspects, all of which relate to certainnon-naturally occurring compounds comprising linked heteroaryl moietieswhich have the generic structure shown below in Formula (I), and methodsfor the synthesis of those compounds, and the use of those compounds andcommestibly acceptable salts and/or compositions thereof as savoryflavoring agents for comestible compositions or one or more of theirprecursor components. In many embodiments, the invention relates tomethods for modulating the savory taste of a comestible productcomprising:

-   -   a) providing at least one comestible product, or one or more        precursors thereof, and    -   b) combining the comestible product or one or more precursors        thereof with at least a savory flavor modulating amount of at        least one compound of Formula (1), or a comestibly acceptable        salt thereof, so as to form a modified comestible product;    -   wherein the compound of Formula (I) has the formula:

-   -   wherein        -   i) Ar is an aryl or heteroaryl radical optionally having at            least one substituent radical bound thereto;        -   ii) Y is O, S, S(O), SO₂, CR¹R², or NR⁵;        -   iii) m is the integer zero or one;        -   iv) hAr¹ is an optionally substituted heteroaryl ring            radical;        -   v) X is O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰;        -   vi) n the integers zero, one, two, or three;        -   vii) hAr² is an optionally substituted heteroaryl ring            radical.

In related embodiments of the compounds of Formula (I), hAr² can be anoptionally substituted aryl radical, such as a phenyl radical.

Additional embodiments of the inventions related to the compounds ofFormula (I) provide for modified comestible products or compositionscomprising one or more of the compounds of Formula (I) or its varioussubgeneric or species compounds or comestibly acceptable salts thereof,or the products produced by the processes recited above, or below. Forexample in further related embodiments, the inventions disclosed hereinrelate to taste modified comestible compositions comprising:

-   -   a) at least one comestible product, or one or more precursors        thereof, and    -   b) at least a savory flavor modulating amount of at least one        compound having the formula:

-   -   wherein        -   i) Ar is a monocyclic or bicyclic aryl or heteroaryl radical            comprising one or two aromatic rings independently selected            from benzene rings and five or six membered heteroaryl            rings, each aromatic ring optionally having one, two, or            three R²⁰ substituent radicals bound thereto, wherein each            R²⁰ radical is independently selected from hydroxyl, NH₂,            NO₂, SH, SO₃H, P(O)(OH)₂, halogen, or a C₁-C₄ organic            radical;        -   ii) hAr¹ is an optionally substituted five or six-membered            heteroaryl ring radical having from 1 to 4 heteroatoms            independently selected from oxygen, sulfur and/or nitrogen,            wherein any remaining members of the heteroaromatic ring are            independently selected from CR⁶, N, NR⁷;        -   iii) X is O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰;        -   iv) n the integer zero, one, two, or three;        -   v) R³, R⁴, R⁸ and R⁹ are independently selected from            hydrogen, oxygen, hydroxyl, NH₂, SH, halogen, or a C₁-C₄            organic radical, and R⁷ and R¹⁰ are independently selected            from hydrogen, hydroxyl, or a C₁-C₄ organic radical, and R⁶            is hydrogen, hydroxyl, NH₂, NO₂, SH, SO₃H, P(O)(OH)₂,            halogen, or a C₁-C₄ organic radical;        -   vi) hAr² is an optionally substituted five or six-membered            heteroaryl ring having at least one ring carbon atom and at            least one ring nitrogen atom, and wherein the remaining            members of the heteroaryl ring are independently selected            from CR³⁰, N, NR³¹, O, and S, wherein each R³⁰ is            independently selected from hydrogen, hydroxyl, NH₂, NO₂,            SH, SO₃H, P(O)(OH)₂, a halogen, or a C₁-C₄ organic radical,            and each R³¹ is independently selected from hydrogen, or a            C₁-C₄ organic radical;    -   or a comestibly acceptable salt thereof.

In some such embodiments, the inventions relate to sub-genuses of thelinked heteroaryl compounds of Formula (I) and their uses in methods formodulating the savory taste of comestible compositions. For example, onesub-genus of the linked heteroaryl compounds has the structure shown inFormula (IA) below:

-   -   wherein        -   i) n′ is the integer zero, one, two, or three, and each R²⁰            is independently selected from the group consisting of            hydroxy, SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   ii) n″ is zero, one, two, or three, and each R³⁰ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   iii) X is NH, O, S, S(O), SO₂, or CH₂,        -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl,            furanyl, thiofuranyl, pyrrolyl, benzofuranyl,            benzothiofuranyl, or benzopyrrolyl ring        -   v) hAr¹ has the structure:

-   -   -   -   (1) X₁ is NH, O, or S,            -   (2) X₂ is N or CR⁶ wherein R⁶ is hydrogen, a halogen, or                a C₁-C₄ organic radical,            -   (3) X₃ is N or CR⁶ wherein R⁶ is hydrogen, a halogen, or                a C₁-C₄ organic radical, and

        -   vi) hAr²is a pyridyl, pyrazinyl, or pyrimidinyl ring;

        -   or a comestibly acceptable salt thereof.

Another related sub-genus of the linked heteroaryls of Formula (I),useful as savory flavoring agents, are triazole compounds having thestructure shown in Formula (IB) below;

-   -   wherein        -   i) n′ is zero, one, two, or three, and each R₂₀ is            independently selected from hydroxy, SH, NH₂, a halogen, and            a C₁-C₄ radical selected from an alkyl, alkoxyl,            alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR²¹,            CO₂R²¹, NHR²¹, NR²¹R^(21′), or SR²¹ radical, wherein R²¹ is            an alkyl,        -   ii) n″ is zero, one, two, or three, and each R₃₀ is            independently selected from hydroxy, SH, NH₂, a halogen, and            a C₁-C₄ radical selected from an alkyl, alkoxyl,            alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR³²,            CO₂R³²NHR³², NR³²R^(32′), or SR³² radical, wherein R³² is an            alkyl,        -   iii) X is NH, O, S, S(O), SO₂, or CH₂,        -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl,            furanyl, thiofuranyl, or pyrrolyl ring;        -   or a comestibly acceptable salt thereof.

Yet another related sub-genus of the linked heteroaryls of Formula (I)are triazole compounds having the structure shown in Formula (IC) belowin which both the X and Y linker groups are present;

-   -   wherein        -   i) n′ is zero, one, two, or three, and each R²⁰ is            independently selected from the group consisting of            hydroxyl, SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   ii) n″ is zero, one, two, or three, and each R³⁰ is            independently selected from the group consisting of OH, SH,            NH₂, a halogen, or a C₁-C₄ organic radical,        -   iii) X is NH, O, S, S(O), SO₂, or CR⁸R⁹, wherein R⁸ and R⁹            are independently selected from hydrogen, oxygen, hydroxyl,            NH₂, a halogen, or a C₁-C₄ organic radical,        -   iv) Y is NH, O, S, S(O), SO₂, or CR⁸R⁹, wherein R⁸ and R⁹            are independently selected from hydrogen, oxygen, hydroxyl,            NH₂, a halogen, or a C₁-C₄ organic radical,        -   v) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl,            thiofuranyl, or pyrrolyl ring;    -   or a comestibly acceptable salt thereof.

Yet another related sub-genus of the linked heteroaryls of Formula (I)are compounds having hAr1 heteroaryl rings that are six-memberednitrogen heteroaryls as shown in Formula (ID):

-   -   wherein        -   i) n′ is zero, one, two, or three, and each R²⁰ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   ii) n″ is zero, one, two, or three, and each R³⁰ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   iii) X is NH, O, S, S(O), SO₂, or CH₂,        -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl,            furanyl, thiofuranyl, pyrrolyl, benzofuranyl,            benzothiofuranyl, or benzopyrrolyl ring        -   v) hAr¹ has the structure

-   -   -    wherein R⁶ and R^(6′) are independently selected from            hydrogen, a halogen, or a C₁-C₄ organic radical, and        -   vi) hAr² is a pyridyl, pyrazinyl, or pyrimidinyl ring.

The linked heteroaryl compounds of Formulas (I), (IA), (IB), (IC), and(ID), and species compounds encompassed therein can bind to and/oractivate the T1R1/T1R3 “savory” (“umami”) taste receptor proteinsin-vitro, at very unexpectedly low concentrations on the order ofmicromolar or lower. The linked heteroaryl compounds are also believedto interact in the same or a similar manner with savory flavor receptorsof animals or humans in vivo, as has been confirmed by actual humantaste tests of selected compounds of Formula (I) that are reportedbelow.

Accordingly, many of the subgenuses and species of the linked heteroarylcompounds of Formula (I) further described herein below can, atunexpectedly low concentrations be used as savory flavoring agents, orsavory enhancers that substitute for and/or synergistically enhance thesavory flavor of MSG.

Additional optional limitations on the chemical and physicalcharacteristics of the heterocyclic compounds of Formula (I) and theirsubstituent radicals or groups will be described below. Some of theheterocyclic compounds with structures encompassed within Formula (I)have been synthesized by methods known in the prior art, for variouspurposes, but to the knowledge of the inventors it has not beenpreviously recognized that such linked heteroaryl compounds can beutilized as savory flavoring agents, or savory taste enhancers. Moreovermany of the heterocyclic compounds of Formula (I) disclosed herein arenovel compounds that have not been previously synthesized at all, andpossess the unexpected property of being savory taste flavoring agentsor taste enhancers.

The invention also relates to flavor modified comestible products, suchas food and drinks, produced by contacting the compounds of theinvention with comestible products or precursors thereof.

In many embodiments, one or more of the linked heteroaryl compounds ofFormula (I) further identified, described, and/or claimed herein, or acomestibly acceptable salt thereof, can be used in mixtures or incombination with other known savory compounds such as MSG, as savoryflavor enhancers in comestible food, and beverage compositions for humanor animal consumption, or their precursors.

In many embodiments, the linked heteroaryl compounds of Formula (I) andits various subgenuses are T1R1/T1R3 receptor agonists and accordinglyare believed to be capable of inducing or enhancing savory tasteperception in humans. Many of the heterocyclic compounds of Formula (I)and/or its various subgenuses of heterocyclic compounds, when usedtogether with MSG or alone, increase or modulate a response in vitro,and savory taste perception in humans at surprisingly lowconcentrations.

In some embodiments, the invention relates to novel compounds, flavoringagents, flavor enhancers, flavor modifying compounds, and/orcompositions containing the compounds of Formula (I), and its varioussubgenuses and species compounds.

In some embodiments, the invention relates to comestible or medicinalcompositions suitable for human or animal consumption, or precursorsthereof, containing at least one compound of Formula (I), or acomestibly acceptable salt thereof.

The foregoing discussion merely summarizes certain aspects of theinventions and is not intended, nor should it be construed, as limitingthe invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be understood more readily by reference to thefollowing detailed description of various embodiments of the inventionand the Examples included therein and to the chemical drawings andTables and their previous and following description. Before the presentcompounds, compositions, and/or methods are disclosed and described, itis to be understood that unless otherwise specifically indicated by theclaims, the invention is not limited to specific foods or foodpreparation methods, specific comestible carriers or formulations, or toparticular modes of formulating the compounds of the invention intocomestible products or compositions intended for oral administration,because as one of ordinary skill in relevant arts is well aware, suchthings can of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting.

Definitions

A “comestibly acceptable carrier or excipient” is a solid or liquidmedium and/or composition that is used to prepare a desired disperseddosage form of the inventive compound, in order to administer theinventive compound in a dispersed/diluted form, so that the biologicaleffectiveness of the inventive compound is maximized. Comestiblyacceptable carriers includes many common food ingredients, such as waterat neutral, acidic, or basic pH, fruit or vegetable juices, vinegar,marinades, beer, wine, natural water/fat emulsions such as milk orcondensed milk, edible oils and shortenings, fatty acids and their alkylesters, low molecular weight oligomers of propylene glycol, glycerylesters of fatty acids, and dispersions or emulsions of such hydrophobicsubstances in aqueous media, salts such as sodium chloride, wheatflours, solvents such as ethanol, solid edible diluents such asvegetable powders or flours, or other liquid vehicles; dispersion orsuspension aids; surface active agents; isotonic agents; thickening oremulsifying agents, preservatives; solid binders; lubricants and thelike.

A “flavor” herein refers to the perception of taste and/or smell in asubject, which include sweet, sour, salty, bitter, umami, and others.The subject may be a human or an animal.

A “flavoring agent” herein refers to a compound or a biologicallyacceptable salt thereof that induces a flavor or taste in an animal or ahuman.

A “flavor modifier” herein refers to a compound or biologicallyacceptable salt thereof that modulates, including enhancing orpotentiating, and inducing, the tastes and/or smell of a natural orsynthetic flavoring agent in an animal or a human.

A “flavor enhancer” herein refers to a compound or biologicallyacceptable salt thereof that enhances and/or multiplies the tastes orsmell of a natural or synthetic flavoring agent, or a comestiblecomposition comprising the flavor enhancer.

“Savory flavor” herein refers to the savory “umami” taste typicallyinduced by MSG (mono sodium glutamate) in an animal or a human.

“Savory flavoring agent,” “savory compound” or “savory receptoractivating compound” herein refers to a compound or biologicallyacceptable salt thereof that elicits a detectable savory flavor in asubject, e.g., MSG (mono sodium glutamate) or a compound that activatesa T1R1/T1R3 receptor in vitro. The subject may be a human or an animal.

A “savory flavor modifier” herein refers to a compound or biologicallyacceptable salt thereof that modulates, including enhancing orpotentiating, inducing, and blocking, the savory taste of a natural orsynthetic savory flavoring agents, e.g., monosodium glutamate (MSG) inan animal or a human.

A “savory flavor enhancer” herein refers to a compound or biologicallyacceptable salt thereof that enhances or potentiates the savory taste ofa natural or synthetic savory flavoring agents, e.g., monosodiumglutamate (MSG) in an animal or a human.

An “umami receptor activating compound” herein refers to a compound thatactivates an umami receptor, such as a T1R1/T1R3 receptor.

An “umami receptor modulating compound” herein refers to a compound thatmodulates (activates, enhances or blocks) an umami receptor.

An “umami receptor enhancing compound” herein refers to a compound thatenhances or potentiates the effect of a natural or synthetic umamireceptor activating compound, e.g., monosodium glutamate (MSG).

A “savory flavor modulating amount” herein refers to an amount of acompound of Formula (I) that is sufficient to alter (either increase ordecrease) savory taste in a comestible or medicinal product orcomposition, or a precursor thereof, sufficiently to be perceived by ahuman subject. In many embodiments of the invention, at least about0.001 ppm of the heterocyclic compound would need to be present in orderfor most human subjects to perceive a modulation of the savory flavor ofa comestible composition comprising the heterocyclic compound. A broadrange of concentration that would typically be employed in order toeconomically provide a desirable degree of savory flavor modulation canbe from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppmto about 10 ppm. Alternative ranges of savory flavor modulating amountscan be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm toabout 3 ppm.

A “savory flavor enhancing amount” herein refers to an amount of acompound that is sufficient to enhance the taste of a natural orsynthetic flavoring agents, e.g., monosodium glutamate (MSG) in acomestible or medicinal product or composition, as perceived by ananimal or a human. A broad range of a savory flavor enhancing amount canbe from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppmto about 10 ppm. Alternative ranges of savory flavor enhancing amountscan be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm toabout 3 ppm.

An “umami receptor modulating amount” herein refers to an amount of acompound that is sufficient to modulate (activate, enhance or block) anumami taste receptor protein. In many embodiments of the invention, anumami receptor modulating amount is at least about 1 pM, or at leastabout 1 nM, or at least about 10 nM, or at least about 100 nM (i.e.about 0.1 μM). A “T1R1/T1R3 receptor modulating or activating amount” isan amount of compound that is sufficient to modulate or activate aT1R1/T1R3 receptor. These amounts are preferably the same as the umamireceptor modulating amounts.

An “umami receptor” is a taste receptor that can be modulated by asavory compound. Preferably an umami receptor is a G protein coupledreceptor, and more preferably the umami receptor is a T1R1/T1R3receptor.

Compounds of the invention modulate an umami receptor and preferably areagonists of the T1R1/T1R3 receptor. An agonist of this receptor has theeffect of activating a G protein signaling cascade. In many cases, thisagonist effect of the compound on the receptor also produces a perceivedsavory flavor in a taste test. It is desirable, therefore, that suchinventive compounds serve as a replacement or enhancer for MSG, which isnot well tolerated by some in, for example, comestible products.

In addition, this agonist effect also is responsible for the synergisticsavory taste effect, which occurs when a compound of the invention iscombined with another savory flavoring agent such as MSG. Thenucleotides, IMP or GMP, are conventionally added to MSG, to intensifythe savory flavor of MSG, so that relatively less MSG is needed toprovide the same savory flavor in comparison to MSG alone. Therefore, itis desirable that combining compounds of the invention with anothersavory flavoring agent such as MSG advantageously eliminates the need toadd expensive nucleotides, such as IMP, as a flavor enhancer, whileconcomitantly reducing or eliminating the amount of a savory compoundsuch as MSG needed to provide the same savory flavor in comparison tothe savory compound or MSG alone.

A “synergistic effect” relates to the enhanced savory flavor of acombination of savory compounds or receptor activating compounds, incomparison to the sum of the taste effects or flavor associated effectsassociated with each individual compound. In the case of savory enhancercompounds, a synergistic effect on the effectiveness of MSG may beindicated for a compound of Formula (I) having an EC50 ratio (definedherein below) of 2.0 or more, or preferably 5.0 or more, or 10.0 ormore, or 15.0 or more.

When the compounds described here include one or more chiral centers,the stereochemistry of such chiral centers can independently be in the Ror S configuration, or a mixture of the two. The chiral centers can befurther designated as R or S or R,S or d,D, l,L or d,l, D,L.Correspondingly, the compounds of the invention, if they can be presentin optically active form, can be present in the form of a racemicmixture of enantiomers, or in the form of either of the separateenantiomers in substantially isolated and purified form, or as a mixturecomprising any relative proportions of the enantiomers. Where soindicated in the claims herein, if a single enantiomer of thepotentially optically active heterocyclic compounds disclosed isdesired, for either health or efficacy reasons, preferably it is presentin an enantiomeric excess of at least about 80%, or at least about 90%,or at least about 95%, or at least about 98%, or at least about 99%, orat least about 99.5%.

As used herein, “hydrocarbon residue” refers to a chemical sub-group orradical within a larger chemical compound which contains only carbon andhydrogen atoms. The hydrocarbon residue may be aliphatic or aromatic,straight-chain, cyclic, branched, saturated or unsaturated. In manyembodiments the hydrocarbon residues are of limited dimensional size andmolecular weight, and may comprise 1 to 18 carbon atoms, 1 to 16 carbonatoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms,1 to 6 carbon atoms, or 1 to 4 carbon atoms.

The hydrocarbon residue, when described as “substituted,” contains or issubstituted with one or more independently selected heteroatoms such asO, S, N, P, or the halogens (fluorine, chlorine, bromine, and iodine),or one or more substituent groups containing heteroatoms (OH, NH₂, NO₂,SO₃H, and the like) over and above the carbon and hydrogen atoms of thesubstituent residue. Substituted hydrocarbon residues may also containcarbonyl groups, amino groups, hydroxyl groups and the like, or containheteroatoms inserted into the “backbone” of the hydrocarbon residue.

As used herein, “inorganic” group or residue refers to a neutral,cationic, or anionic radical substituents on the organic moleculesdisclosed or claimed herein that have from one to 16 atoms that do notinclude carbon, but do contain other heteroatoms from the periodic tablethat preferably include one or more atoms independently selected fromthe group consisting of H, O, N, S, one or more halogens, or alkalimetal or alkaline earth metal ions. Examples of inorganic radicalsinclude, but are not limited to H, Na+, Ca++ and K+, halogens whichinclude fluorine, chlorine, bromine, and iodine, OH, SH, SO₃H, SO₃ ⁻,PO₃H, PO₃ ⁻, NO, NO₂ or NH₂, and the like.

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight- and branched-chain and cyclic monovalent substituents thatrespectively are saturated, unsaturated with at least one double bond,and unsaturated with at least one triple bond.

“Alkyl” refers to a hydrocarbon group that can be conceptually formedfrom an alkane by removing hydrogen from the structure of a non-cyclichydrocarbon compound having straight or branched carbon chains, andreplacing the hydrogen atom with another atom or organic or inorganicsubstitutent group. In some embodiments of the invention, the alkylgroups are “C₁ to C₆ alkyl” such as methyl, ethyl, propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl andthe like. Many embodiments of the invention comprise “Cl to C₄ alkyl”groups (alternatively termed “lower alkyl” groups) that include methyl,ethyl, propyl, iso-propyl n-butyl, iso-butyl, sec-butyl, and t-butylgroups. Some of the preferred alkyl groups of the invention have threeor more carbon atoms preferably 3 to 16 carbon atoms, 4 to 14 carbonatoms, or 6 to 12 carbon atoms.

The term “alkenyl” is structurally analogous to an alkyl group orresidue that comprises at least one carbon-carbon double bond. In someembodiments, alkenyl groups are “C₂ to C₇ alkenyls” which areexemplified by vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well asdienes and trienes of straight and branched chains. In otherembodiments, alkenyls are limited to two to four carbon atoms.

The term “alkynyl” is analogous to an alkyl group or radical thatcomprises at least one carbon-carbon triple bond. Preferred alkynylgroups are “C₂ to C₇ alkynyl” such as ethynyl, propynyl, 2-butynyl,2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 5-heptynyl as well as di- and tri-ynes ofstraight and branched chains including ene-ynes.

The terms “substituted alkyl,” “substituted alkenyl,” “substitutedalkynyl,” and “substituted alkylene” denote that the alkyl, alkenyl, oralkynyl groups or radicals as described herein, wherein one or morehydrogen atoms has been conceptually substituted by one or more, andpreferably one or two independently selected organic or inorganicsubstituent groups or radicals, that can include a halogen, hydroxy,amino, SH, a C₁ to C₇ alkoxy, or alkoxy-alkyl, oxo, C₃ to C₇ cycloalkyl,naphthyl, amino, (monosubstituted)amino, (disubstituted)amino,guanidino, heterocycle, substituted heterocycle, imidazolyl, indolyl,pyrrolidinyl, C₁ to C₇ acyl, C₁ to C₇ acyloxy, nitro, carboxy,carbamoyl, carboxamide, N-(C₁ to C₆ alkyl)carboxamide, N,N-di(C₁ to C₆alkyl)carboxamide, cyano, methylsulfonylamino, thiol, C₁ to C₄ alkylthioor C₁ to C₄ alkylsulfonyl groups. The substituted alkyl groups may besubstituted once or more, and preferably once or twice, with the same orwith different substituents. In many embodiments of the invention, apreferred group of substituent groups for a substantial alkyls includehydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl,ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy,and trifluoromethoxy groups. In many embodiments of the invention thatcomprise the above lists of substituent groups, an even more preferredgroup of substituent groups include hydroxy, SEt, SCH₃, methyl, ethyl,isopropyl, trifluromethyl, methoxy, ethoxy, and trifluoromethoxy groups.

Examples of the above substituted alkyl groups include the2-oxo-prop-1-yl, 3-oxo-but-1-yl, cyanomethyl, nitromethyl, chloromethyl,trifluoromethyl, hydroxymethyl, tetrahydropyranyloxymethyl,trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl,allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl,ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl,trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-aminopropyl,1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-chloroethyl,1-fluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodoethyl, 1-chloropropyl,2-chloropropyl, 3-chloropropyl, 1-bromopropyl, 2-bromopropyl,3-bromopropyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl,2-aminoethyl, 1-aminoethyl, N-benzoyl-2-aminoethyl,N-acetyl-2-aminoethyl, N-benzoyl-1-aminoethyl, N-acetyl-1-aminoethyl andthe like.

Examples of substituted alkenyl groups include styrenyl,3-chloro-propen-1-yl, 3-chloro-buten-1-yl, 3-methoxy-propen-2-yl,3-phenyl-buten-2-yl, 1-cyano-buten-3-yl and the like. The geometricalisomerism is not critical, and all geometrical isomers for a givensubstituted double bond can be included.

Examples of substituted alkynyl groups include phenylacetylen-1-yl,1-phenyl-2-propyn-1-yl and the like.

Haloalkyls are substituted alkyl groups or residues wherein one or morehydrogens of the corresponding alkyl group have been replaced with ahalogen atom (fluorine, chlorine, bromine, and iodine). Preferredhaloalkyls can have one to four carbon atoms. Examples of preferredhaloalkyl groups include trifluoromethyl and pentafluoroethyl groups.

Haloalkoxy groups are alkoxy groups or residues wherein one or morehydrogens from the R group of the alkoxy group are a halogen atom(fluorine, chlorine, bromine, and iodine). Preferred haloalkoxy groupscan have one to four carbon atoms. Examples of preferred haloalkoxygroups include trifluoromethyoxy and pentafluoroethoxy groups.

The term “oxo” denotes a carbon atom bonded to two additional carbonatoms substituted with an oxygen atom doubly bonded to the carbon atom,thereby forming a ketone radical or residue.

“Alkoxy” or “alkoxyl” refers to an —OR radical or group, wherein R is analkyl radical. In some embodiments the alkoxy groups can be C₁ to C₈,and in other embodiments can be C₁ to C₄ alkoxy groups wherein R is alower alkyl, such as a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,t-butoxy and like alkoxy groups. The term “substituted alkoxy” meansthat the R group is a substituted alkyl group or residue. Examples ofsubstituted alkoxy groups include trifluoromethoxy, hydroxymethyl,hydroxyethyl, hydroxypropyl, and alkoxyalkyl groups such asmethoxymethyl, methoxyethyl, polyoxoethylene, polyoxopropylene, andsimilar groups.

“Alkoxyalkyl” refers to an —R—O—R′ group or radical, wherein R and R′are alkyl groups. In some embodiments the alkoxyalkyl groups can be C₁to C₈, and in other embodiments can be C₁ to C₄. In many embodiments,both R and R′ are a lower alkyl, such as a methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy and like alkoxy groups. Examples ofalkoxyalkyl groups include, methoxymethyl, ethoxyethyl, methoxypropyl,and methoxybutyl and similar groups.

“Acyloxy” refers to an RCO₂— ester group where R is an alkyl,cycloalkyl, aryl, heteroaryl, substituted alkyl, substituted cycloalkyl,substituted aryl, or substituted heteraryl group or radical wherein theR radical comprises one to seven or one to four carbon atoms. In manyembodiments, R is an alkyl radical, and such acyloxy radicals areexemplified by formyloxy, acetoxy, propionyloxy, butyryloxy,pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like. Inother embodiments the R groups are C₁-C₄ alkyls.

As used herein, “acyl” encompasses the definitions of alkyl, alkenyl,alkynyl and the related hetero-forms which are coupled to an additionalorganic residue through a carbonyl group to form a ketone radical orgroup. Preferred acyl groups are “C₁ to C₇ acyl” such as formyl, acetyl,propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyland the like. More preferred acyl groups are acetyl and benzoyl.

The term “substituted acyl” denotes an acyl group wherein the R groupsubstituted by one or more, and preferably one or two, halogen, hydroxy,oxo, alkyl, cycloalkyl, naphthyl, amino, (monosubstituted)amino,(disubstituted)amino, guanidino, heterocyclic ring, substitutedheterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C₁ to C₇ alkoxy,alkoxy-alkyl, C₁ to C₇ acyl, C₁ to C₇ acyloxy, nitro, C₁ to C₆ alkylester, carboxy, alkoxycarbonyl, carbamoyl, carboxamide, N—(C₁ to C₆alkyl)carboxamide, N,N-di(C₁ to C₆ alkyl)carboxamide, cyano,methylsulfonylamino, thiol, C₁ to C₄ alkylthio or C₁ to C₄ alkylsulfonylgroups. The substituted acyl groups may be substituted once or more, andpreferably once or twice, with the same or with different substituents.

Examples of C₁ to C₇ substituted acyl groups include 4-phenylbutyroyl,3-phenylbutyroyl, 3 phenylpropanoyl, 2- cyclohexanylacetyl,cyclohexanecarbonyl, 2-furanoyl and 3 dimethylaminobenzoyl.

Cycloalkyl residues or groups are structurally related to cyclicmonocyclic or bicyclic hydrocarbon compounds wherein one or morehydrogen atoms has been replaced with an organic or inorganicsubstituent group. The cycloalkyls of the current inventions comprise atleast 3 up to 12, or more preferably 3 to 8 ring carbon atoms, or morepreferably 4 to 6 ring carbon atoms. Examples of such cyclalkyl residuesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl rings, and saturated bicyclic or fused polycycliccycloalkanes such as decalin groups, polycyclic norbornyl or adamantlygroups, and the like.

Preferred cycloalkyl groups include “C₃ to C₇ cycloalkyl” such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.Similarly, the term “C₅ to C₇ cycloalkyl” includes cyclopentyl,cyclohexyl or cycloheptyl rings.

“Substituted cycloalkyl” denote a cycloalkyl rings as defined above,substituted by 1 to four, or preferably one or two substituentsindependently selected from a halogen, hydroxy, C₁ to C₄ alkylthio, C₁to C₄ alkylsulfoxide, C₁ to C₄ alkylsulfonyl, C₁ to C₄ substitutedalkylthio, C₁ to C₄ substituted alkylsulfoxide, C₁ to C₄ substitutedalkylsulfonyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₁ to C₆ substitutedalkyl, C₁ to C₄ alkoxy-alkyl, oxo (monosubstituted)amino,(disubstituted)amino, trifluoromethyl, carboxy, phenyl, substitutedphenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino. In manyembodiments of substituted cycloalkyl groups, the substituted cycloalkylgroup will have 1, 2, 3, or 4 substituent groups independently selectedfrom hydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃,methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy groups.

The term “cycloalkylene” means a cycloalkyl, as defined above, where thecycloalkyl radical is bonded at two positions connecting together twoseparate additional groups. Similarly, the term “substitutedcycloalkylene” means a cycloalkylene where the cycloalkyl radical isbonded at two positions connecting together two separate additionalgroups and further bearing at least one additional substituent.

The term “cycloalkenyl” indicates preferably a 1, 2, or 3-cyclopentenylring, a 1, 2, 3 or 4-cyclohexenyl ring or a 1, 2, 3, 4 or5-cycloheptenyl ring, while the term “substituted cycloalkenyl” denotesthe above cycloalkenyl rings substituted with a substituent, preferablyby a C₁ to C₆ alkyl, halogen, hydroxy, C₁ to C₇ alkoxy, alkoxy-alkyl,trifluoromethyl, carboxy, alkoxycarbonyl oxo, (monosubstituted)amino,(disubstituted)amino, phenyl, substituted phenyl, amino, or protectedamino.

The term “cycloalkenylene” is a cycloalkenyl ring, as defined above,where the cycloalkenyl radical is bonded at two positions connectingtogether two separate additional groups. Similarly, the term“substituted cycloalkenylene” means a cycloalkenylene furthersubstituted preferably by halogen, hydroxy, C₁ to C₄ alkylthio, C₁ to C₄alkylsulfoxide, C₁ to C₄ alkylsulfonyl, C₁ to C₄ substituted alkylthio,C₁ to C₄ substituted alkylsulfoxide, C₁ to C₄ substituted alkylsulfonyl,C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₆ substituted alkyl, C₁ to C₇alkoxy-alkyl, oxo, (monosubstituted)amino, (disubstituted)amino,trifluoromethyl, carboxy, alkoxycarbonyl, phenyl, substituted phenyl,phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or substituted aminogroup.

The term “heterocycle” or “heterocyclic ring” denotes optionallysubstituted 3 to 8-membered rings having one or more carbon atomsconnected in a ring that also comprise 1 to 5 ring heteroatoms, such asoxygen, sulfur and/or nitrogen inserted into the ring. Theseheterocyclic rings can be saturated, unsaturated or partiallyunsaturated, but are preferably saturated. Preferred unsaturatedheterocyclic rings include furanyl, thiofuranyl, pyrrolyl, pyridyl,pyrimidyl, pyrazinyl, benzoxazole, benzthiazole, quinolinlyl, and likeheteroaromatic rings. Preferred saturated heterocyclic rings includepiperidyl, aziridinyl, piperidinyl, piperazinyl, tetrahydrofurano,pyrrolyl, and tetrahydrothiophen-yl.rings.

The term “substituted heterocycle” or “substituted heterocyclic ring”means the above-described heterocyclic ring is substituted with, forexample, one or more, and preferably one or two, substituents which arethe same or different which substituents preferably can be halogen,hydroxy, thio, alkylthio, cyano, nitro, C₁ to C₄ alkyl, C₁ to C₄ alkoxy,C₁ to C₄ substituted alkoxy, alkoxy-alkyl, C₁ to C₄ acyl, C₁ to C₄acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl,alkoxy-alkyl amino, monosubstituted)amino, (disubstituted)aminocarboxamide, N—(C₁ to C₆ alkyl)carboxamide, N,N-di(C₁ to C₆alkyl)carboxamide, trifluoromethyl, N—((C₁ to C₆ alkyl)sulfonyl)amino,N-(phenylsulfonyl)amino groups, or substituted with a fused ring, suchas benzo-ring. In many embodiments of substituted heterocyclic groups,the substituted cycloalkyl group will have 1, 2, 3, or 4 substituentgroups independently selected from hydroxy, fluoro, chloro, NH₂, NHCH₃,N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl, isopropyl, vinyl,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxygroups.

An “aryl” group refers to a monocyclic, linked bicyclic or fusedbicyclic radical or group comprising at least one six membered aromatic“benzene” ring. Aryl groups preferably comprise between 6 and 12 ringcarbon atoms, and are exemplified by phenyl, biphenyl, naphthyl,indanyl, and tetrahydronapthyl groups. Aryl groups can be optionallysubstituted with various organic and/or inorganic substitutent groups,wherein the substituted aryl group in combination with all itssubstituents comprise between 6 and 18, or preferably 6 and 16 totalcarbon atoms. Preferred optional substituent groups include 1, 2, 3, or4 substituent groups independently selected from hydroxy, fluoro,chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl,isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy groups.

The term “heteroaryl” means a heterocyclic aryl derivative whichpreferably contains a five-membered or six-membered conjugated andaromatic ring system having from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and/or nitrogen, inserted into theunsaturated and conjugated heterocyclic ring. Heteroaryl groups includemonocyclic heteroaromatic, linked bicyclic heteroaromatic or fusedbicyclic heteroaromatic moieties. Examples of heteroaryls includepyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolyl, furanyl,thiofuranyl, oxazoloyl, isoxazolyl, phthalimido, thiazolyl, quinolinyl,isoquinolinyl, indolyl, or a furan or thiofuran directly bonded to aphenyl, pyridyl, or pyrrolyl ring and like unsaturated and conjugatedheteroaromatic rings. Any monocyclic, linked bicyclic, or fused bicyclicheteroaryl ring system which has the characteristics of aromaticity interms of electron distribution throughout the ring system is included inthis definition. Typically, the heteroaromatic ring systems contain 3-12ring carbon atoms and 1 to 5 ring heteroatoms independently selectedfrom oxygen, nitrogen, and sulfur atoms.

The term “substituted heteroaryl” means the above-described heteroarylis substituted with, for example, one or more, and preferably one ortwo, substituents which are the same or different which substituentspreferably can be halogen, hydroxy, protected hydroxy, thio, alkylthio,cyano, nitro, C₁ to C₆ alkyl, C₁ to C₇ substituted alkyl, C₁ to C₇alkoxy, C₁ to C₇ substituted alkoxy, alkoxy-alkyl, C₁ to C₇ acyl, C₁ toC₇ substituted acyl, C₁ to C₇ acyloxy, carboxy, alkoxycarbonyl,carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino,(disubstituted)amino, carboxamide, N—(C1 to C6 alkyl)carboxamide,N,N-di(C1 to C6 alkyl)carboxamide, trifluoromethyl, N—((C1 to C6alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino groups. In manyembodiments of substituted heteroaryl groups, the substituted cycloalkylgroup will have 1, 2, 3, or 4 substituent groups independently selectedfrom hydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃,methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy groups.

Similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1-6C. These carbon chains mayalso include a carbonyl group, thus making them able to providesubstituents as an acyl moiety. Preferably, arylalkyl or heteroarylalkylis an alkyl group substituted at any position by an aryl group,substituted aryl, heteroaryl or substituted heteroaryl. Preferred groupsalso include benzyl, 2-phenylethyl, 3-phenyl-propyl, 4-phenyl-n-butyl,3-phenyl-n-amyl, 3-phenyl-2-butyl, 2-pyridinylmethyl,2-(2-pyridinyl)ethyl, and the like.

The term “substituted arylalkyl” denotes an arylalkyl group substitutedon the alkyl portion with one or more, and preferably one or two, groupspreferably chosen from halogen, hydroxy, oxo, amino,(monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclicring, substituted heterocyclic ring, C₁ to C₆ alkyl, C₁ to C₆substituted alkyl, C₁ to C₇ alkoxy, C₁ to C₇ substituted alkoxy,alkoxy-alkyl, C₁ to C₇ acyl, C₁ to C₇ substituted acyl, C₁ to C₇acyloxy, nitro, carboxy, alkoxycarbonyl, carbamoyl, carboxamide, N—(C₁to C₆ alkyl)carboxamide, N,N—(C₁ to C₆ dialkyl)carboxamide, cyano, N—(C₁to C₆ alkylsulfonyl)amino, thiol, C₁ to C₄ alkylthio, C₁ to C₄alkylsulfonyl groups; and/or the phenyl group may be substituted withone or more, and preferably one or two, substituents preferably chosenfrom halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro,C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₁ to C₇ alkoxy, C₁ to C₇substituted alkoxy, alkoxy-alkyl, C₁ to C₇ acyl, C₁ to C₇ substitutedacyl, C₁ to C₇ acyloxy, carboxy, alkoxycarbonyl, carboxymethyl,hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino,carboxamide, N—(C₁ to C₆ alkyl) carboxamide, N,N-di(C₁ to C₆alkyl)carboxamide, trifluoromethyl, N—((C1 to C6 alkyl)sulfonyl)amino,N-(phenylsulfonyl)amino, cyclic C₂ to C₇ alkylene or a phenyl group,substituted or unsubstituted, for a resulting biphenyl group. Thesubstituted alkyl or phenyl groups may be substituted with one or more,and preferably one or two, substituents which can be the same ordifferent.

Examples of the term “substituted arylalkyl” include groups such as2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxyphenyl)-n-hexyl, 2-(5-cyano-3-methoxyphenyl)-n-pentyl,3-(2,6-dimethylphenyl)propyl, 4-chloro-3-aminobenzyl,6-(4-methoxyphenyl)-3-carboxy-n-hexyl,5-(4-aminomethylphenyl)-3-(aminomethyl)-n-pentyl,5-phenyl-3-oxo-n-pent-1-yl and the like.

The term “arylalkylene” specifies an arylalkyl, as defined above, wherethe arylalkyl radical is bonded at two positions connecting together twoseparate additional groups. The definition includes groups of theformula: -phenyl-alkyl- and alkyl-phenyl-alkyl-. Substitutions on thephenyl ring can be 1,2, 1,3 or 1,4. The term “substituted arylalkylene”is an arylalkylene as defined above that is further substitutedpreferably by halogen, hydroxy, protected hydroxy, C₁ to C₄ alkylthio,C₁ to C₄ alkylsulfoxide, C₁ to C₄ alkylsulfonyl, C₁ to C₄ substitutedalkylthio, C₁ to C₄ substituted alkylsulfoxide, C₁ to C₄ substitutedalkylsulfonyl, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₆ substitutedalkyl, C₁ to C₇ alkoxy-alkyl, oxo, (monosubstituted)amino,(disubstituted)amino, trifluoromethyl, carboxy, alkoxycarbonyl, phenyl,substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino,or protected amino group on the phenyl ring or on the alkyl group.

The term “substituted phenyl” specifies a phenyl group substituted withone or more, and preferably one or two, moieties preferably chosen fromthe groups consisting of halogen, hydroxy, protected hydroxy, thio,alkylthio, cyano, nitro, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₁to C₇ alkoxy, C₁ to C₇ substituted alkoxy, alkoxy-alkyl, C₁ to C₇ acyl,C₁ to C₇ substituted acyl, C₁ to C₇ acyloxy, carboxy, alkoxycarbonyl,carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino,(disubstituted)amino, carboxamide, N—(C₁ to C₆ alkyl)carboxamide,N,N-di(C₁ to C₆ alkyl)carboxamide, trifluoromethyl, N—((C₁ to C₆alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or phenyl, wherein thephenyl is substituted or unsubstituted, such that, for example, abiphenyl results. In many embodiments of substituted phenyl groups, thesubstituted cycloalkyl group will have 1, 2, 3, or 4 substituent groupsindependently selected from hydroxy, fluoro, chloro, NH₂, NHCH₃,N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl, isopropyl, vinyl,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxygroups.

The terms “halo” and “halogen” refer to fluoro, chloro, bromo or iodoatoms or ions. Preferred halogens are chloro and fluoro. Although manyof the compounds of the invention having halogen atoms as substituentsare highly effective in binding to the relevant Umami taste receptors,such halogenated organic compounds can in some cases have undesirabletoxicological properties when administered to an animal in vivo.Therefore, in the various embodiments of the compounds of Formula (I),if a halogen atom (including a fluoro, chloro, bromo, or iodo atom) islisted as a possible substitutent, an alternative and preferred group ofsubstitutents expressly contemplated hereby would NOT include thehalogen groups.

The term “(monosubstituted)amino” refers to an amino (NHR) group whereinthe R group is chosen from the group consisting of phenyl, C₆-C₁₀substituted phenyl, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₁ to C₇acyl, C₁ to C₇ substituted acyl, C₂ to C₇ alkenyl, C₂ to C₇ substitutedalkenyl, C₂ to C₇ alkynyl, C₂ to C₇ substituted alkynyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl and heterocyclic ring.The (monosubstituted)amino can additionally have an amino-protectinggroup as encompassed by the term “protected (monosubstituted)amino.”

The term “(disubstituted)amino” refers to an amino group (NR₂) with twosubstituents independently chosen from the group consisting of phenyl,C₆-C₁₀ substituted phenyl, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl,C₁ to C₇ acyl, C₂ to C₇ alkenyl, C₂ to C₇ alkynyl, C₇ to C₁₂phenylalkyl, and C₇ to C₁₂ substituted phenylalkyl. The two substituentscan be the same or different.

The term “alkylthio” refers to —SR groups wherein R is an optionallysubstituted C₁-C₇ or C₁-C₄ organic group, preferably an alkyl,cycloalkyl, aryl, or heterocyclic group, such as methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.

The term “alkylsulfoxide” indicates —SO₂R groups wherein R is anoptionally substituted C₁-C₇ or C₁-C₄ organic group, preferably analkyl, cycloalkyl, aryl, or heterocyclic group, such as methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio andlike groups ,such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide,isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide and the like.

The term “alkylsulfonyl” indicates —S(O)R groups wherein R is anoptionally substituted C₁-C₇ or C₁-C₄ organic group, which include forexample groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like.

The terms “phenylthio,” “phenylsulfoxide,” and “phenylsulfonyl” specifya sulfoxide (—S(O)—R), or sulfone (—SO₂R) wherein the R group is aphenyl group. The terms “substituted phenylthio,” “substitutedphenylsulfoxide,” and “substituted phenylsulfonyl” means that the phenylof these groups can be substituted as described above in relation to“substituted phenyl.”

The term “alkoxycarbonyl” means an “alkoxy” group attached to a carbonylgroup, (i.e. a carboxylic acid ester, —C(O)—OR, wherein R is preferablyan alkyl group, preferably a C₁-C₄ alkyl group. The term “substitutedalkoxycarbonyl” denotes a substituted alkoxy bonded to the carbonylgroup, which alkoxy may be substituted as described above in relation tosubstituted alkyl.

The term “phenylene” means a phenyl group where the phenyl radical isbonded at two positions connecting together two separate additionalgroups. Examples of “phenylene” includes 1,2-phenylene, 1,3-phenylene,and 1,4-phenylene.

The term “substituted alkylene” means an alkyl group where the alkylradical is bonded at two positions connecting together two separateadditional groups and further bearing an additional substituent.Examples of “substituted alkylene” includes aminomethylene,1-(amino)-1,2-ethyl, 2-(amino)-1,2-ethyl, 1-(acetamido)-1,2-ethyl,2-(acetamido)-1,2-ethyl, 2-hydroxy-1,1-ethyl, 1-(amino)-1,3-propyl.

One or more of the compounds of the invention, may be present as a salt.The term “salt” encompasses those salts that form with the carboxylateanions and amine nitrogens and include salts formed with the organic andinorganic anions and cations discussed below. Furthermore, the termincludes salts that form by standard acid-base reactions with basicgroups (such as nitrogen containing heterocycles or amino groups) andorganic or inorganic acids. Such acids include hydrochloric,hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic,citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic,D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic,salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic,cinnamic, and like acids.

The term “organic or inorganic cation” refers to positively chargedcounter-ions for the carboxylate anion of a carboxylate salt. Inorganicpositively charged counter-ions include but are not limited to thealkali and alkaline earth metals, (such as lithium, sodium, potassium,calcium, magnesium, etc.) and other divalent and trivalent metalliccations such as barium, aluminum and the like, and ammonium (NH₄)⁺cations. Organic cations include ammonium cations derived from acidtreatment or alkylation of primary-, secondary, or tertiary amines suchas trimethylamine, cyclohexylamine; and the organic cations, such asdibenzylammonium, benzylammonium, 2-hydroxyethylammonium,bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium,dibenzylethylenediammonium, and like cations. See, for example,“Pharmaceutical Salts,” Berge, et al., J. Pharm. Sci. (1977) 66:1-19,which is incorporated herein by reference. Other cations encompassed bythe above term include the protonated form of procaine, quinine andN-methylglucosamine, and the protonated forms of basic amino acids suchas glycine, ornithine, histidine, phenylglycine, lysine and arginine.Furthermore, any zwitterionic form of the instant compounds formed by acarboxylic acid and an amino group is referred to by this term. Forexample, a cation for a carboxylate anion will exist when R² or R³ issubstituted with a (quaternary ammonium)methyl group. A preferred cationfor the carboxylate anion is the sodium cation.

The compounds of the invention can also exist as solvates and hydrates.Thus, these compounds may crystallize with, for example, waters ofhydration, or one, a number of, or any fraction thereof of molecules ofthe mother liquor solvent. The solvates and hydrates of such compoundsare included within the scope of this invention.

The term “amino acid” includes any one of the twenty naturally-occurringamino acids or the D-form of any one of the naturally-occurring aminoacids. In addition, the term “amino acid” also includes othernon-naturally occurring amino acids besides the D-amino acids, which arefunctional equivalents of the naturally-occurring amino acids. Suchnon-naturally-occurring amino acids include, for example, norleucine(“Nle”), norvaline (“Nva”), L- or D-naphthalanine, ornithine (“Orn”),homoarginine (homoArg) and others well known in the peptide art, such asthose described in M. Bodanzsky, “Principles of Peptide Synthesis,” 1stand 2nd revised ed., Springer-Verlag, New York, N.Y., 1984 and 1993, andStewart and Young, “Solid Phase Peptide Synthesis,” 2nd ed., PierceChemical Co., Rockford, Ill., 1984, both of which are incorporatedherein by reference. Amino acids and amino acid analogs can be purchasedcommercially (Sigma Chemical Co.; Advanced Chemtech) or synthesizedusing methods known in the art.

A residue of a chemical species, as used in the specification andconcluding claims, refers to a structural fragment, or a moiety that isthe resulting product of the chemical species in a particular reactionscheme or subsequent formulation or chemical product, regardless ofwhether the structural fragment or moiety is actually obtained from thechemical species. Thus, an ethylene glycol residue in a polyester refersto one or more —OCH₂CH₂O— repeat units in the polyester, regardless ofwhether ethylene glycol is used to prepare the polyester.

The term “organic residue” or “organic radical” defines a carboncontaining residue or radical, comprising at least one carbon atom.Organic residues can contain one or more heteroatoms, or be bonded toanother molecule through a heteroatom, including oxygen, nitrogen,sulfur, phosphorus, or the like. Examples of organic residues includebut are not limited alkyl or substituted alkyls, alkoxyls or substitutedalkoxyls, hydroxyalkyls and alkoxyalkyls, cycloalkyl or substitutedcycloalkyls, cycloalkenyl or substituted cycloalkyenyls, heterocyclesand substituted heterocycles, aryls and substituteed aryls, heteroarylsand substituted heteroaryls, mono or di-substituted amino, amide groups,CN, CO₂H, CHO, COR⁶, CO₂R⁶′SR⁶ wherein R⁶ is an alkyl, and the like.Examples of species of organic groups or residues include but are notlimited to NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl, isopropyl,vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy,phenyl, phenoxyl, and pyridyl groups or residues, and the like. Organicresidues can comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms.

By the term “effective amount” of a compound as provided herein is meanta sufficient amount of the compound to provide the desired regulation ofa desired function, such as gene expression, protein function, or theinduction of a particular type of taste perception. As will be pointedout below, the exact amount required will vary from subject to subject,depending on the species, age, general condition of the subject,specific identity and formulation of the comestible composition, etc.Thus, it is not possible to specify an exact “effective amount.”However, an appropriate effective amount can be determined by one ofordinary skill in the art using only routine experimentation.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an aromatic compound” includes mixtures of aromaticcompounds.

Often, ranges are expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms another embodiment. Itwill be further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not. For example, the phrase “optionally substituted lower alkyl”means that the lower alkyl group may or may not be substituted and thatthe description includes both unsubstituted lower alkyl and lower alkylswhere there is substitution.

The Linked Heteroaryl Compounds of the Invention

While not wishing to be bound by theory, the linked heteroaryl compoundsdescribed herein are believed to be agonists and/or allosteric modifiersof umami taste receptor proteins. Accordingly, it is reasonable tobelieve that the linked heteroaryl compounds have a core of linkedstructural elements which when considered as a whole, and despite somepossible variability in each of the individual structural elements ortheir peripheral substitutents, have a size, shape, and/or polarity thatallows for significant and specific attractive interactions with theumami taste receptor proteins, so that the linked heteroaryl compoundscan modify, improve, and/or enhance the umami taste of comestibleproducts intended for animal and/or human consumption. Accordingly, thelinked heteroaryl compounds, while they may differ in some respects,nevertheless share certain structural features that, to somewhat varyingdegrees, promote desirable agonistic or allosteric binding interactionswith the umami taste receptor proteins.

Accordingly, the compounds of the invention all comprise at least twoaromatic “aryl” or “heteroaryl” groups hAr¹ and hAr², and a third arylor heteroaryl ring group Ar, all three of which aromatic ring groups canbe optionally substituted by a variety of peripheral substitutents.Moreover, the hAr¹, hAr² and Ar ring groups are linked together bybridging or linking groups X, Y, and/or CR₃R₄ as further defined below,which may be present in defined but variable numbers, or in some casesoptionally absent. More specifically, the compounds of the invention(the “linked heteroaryl compounds”) are a genus of compounds which sharea core of structural features shown in Formula (I) below:

-   -   wherein the various groups can be defined, and/or selected in        alternate and various ways, as shown in the Summary of the        Invention section above, or below.

In some embodiments of the linked heteroaryl compounds of Formula (I):

-   -   i) Ar is a monocyclic or bicyclic aryl or heteroaryl radical        comprising one or two aromatic rings independently selected from        benzene rings and five or six membered heteroaryl rings, each        aromatic ring optionally having one or two R²⁰ substituent        radicals bound thereto, wherein each R²⁰ radical is        independently selected from hydroxyl, NH₂, SH, halogen, or a        C₁-C₄ organic radical;    -   ii) Y is O, S, S(O), SO₂, CR¹R², or NR⁵;    -   iii) m is the integer zero or one;    -   iv) hAr¹ is a five or six-membered heteroaryl ring radical        comprising at least two ring carbon atoms and one to three ring        heteroatoms independently selected from O, N, or S, wherein any        remaining members of the heteroaromatic ring are independently        selected from from CR⁶, N, NR⁷;    -   v) X is O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰;    -   vi) n is the integer zero, one, two, or three;    -   vii) R¹, R², R³, R⁴, R⁸ and R⁹ are independently selected from        hydrogen, oxygen, hydroxyl, NH₂, SH, halogen, or a C₁-C₄ organic        radical, and R⁵, R⁷ and R¹⁰ are independently selected from        hydrogen, hydroxyl, or a C₁-C₄ organic radical, and R⁶ is        hydrogen, halogen, or a C₁-C₄ organic radical;    -   viii) hAr² is a five or six-membered heteroaryl ring having at        least two ring carbon atoms and at least one ring nitrogen atom,        and wherein the remaining members of the heteroaromatic ring are        independently selected from CR³⁰, N, NR³¹, O, and S, wherein        each R³⁰ is independently selected from hydrogen, a halogen, or        a C₁-C₄ organic radical and each R³¹ is independently selected        from hydrogen, or a C₁-C₄ organic radical;

or a comestibly acceptable salt thereof.

In closely related embodiments of the linked heteroaryl compounds ofFormula (I) wherein hAr² is an aryl ring:

-   -   i) Ar is a monocyclic or bicyclic aryl or heteroaryl radical        comprising one or two aromatic rings independently selected from        benzene rings and five or six membered heteroaryl rings, each        aromatic ring optionally having one or two R²⁰ substituent        radicals bound thereto, wherein each R²⁰ radical is        independently selected from hydroxyl, NH₂, SH, halogen, or a        C₁-C₄ organic radical;    -   ii) Y is O, S, S(O), SO₂, CR¹R², or NR⁵;    -   iii) m is the integer zero or one;    -   iv) hAr¹ is a five or six-membered heteroaryl ring radical        comprising at least two ring carbon atoms and one to three ring        heteroatoms independently selected from O, N, or S, wherein any        remaining members of the heteroaromatic ring are independently        selected from from CR⁶, N, NR⁷;    -   v) X is O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰;    -   vi) n is the integer zero, one, two, or three;    -   vii) R¹, R², R³, R⁴, R⁸ and R⁹ are independently selected from        hydrogen, oxygen, hydroxyl, NH₂, SH, halogen, or a C₁-C₄ organic        radical, and R⁵, R⁷ and R¹⁰ are independently selected from        hydrogen, hydroxyl, or a C₁-C₄ organic radical, and R⁶ is        hydrogen, halogen, or a C₁-C₄ organic radical;    -   viii) hAr² is a phenyl ring optionally substituted with 0, 1, 2,        or 3 R³⁰ radicals independently selected from hydrogen, a        halogen, or a C₁-C₄ organic radical;

or a comestibly acceptable salt thereof.

Other related embodiments of the invention provide for taste modifiedcomestible compositions comprising at least a savory flavor modulatingamount of at least one compound of Formula I that do not comprise the“Y” groups of the compounds of Formula I and therefore have the formula:

wherein

-   -   i) Ar is a monocyclic or bicyclic aryl or heteroaryl radical        comprising one or two aromatic rings independently selected from        benzene rings and five or six membered heteroaryl rings, each        aromatic ring optionally having one, two, or three R²⁰        substituent radicals bound thereto, wherein each R²⁰ radical is        independently selected from hydroxyl, NH₂, NO₂, SH, SO₃H,        P(O)(OH)₂, halogen, or a C₁-C₄ organic radical;    -   ii) hAr¹ is a five or six-membered heteroaryl ring radical        having from 1 to 4 heteroatoms independently selected from        oxygen, sulfur and/or nitrogen, wherein any remaining members of        the heteroaromatic ring are independently selected from CR⁶, N,        NR⁷;    -   iii) X is O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰;    -   iv) n the integer zero, one, two, or three;    -   v) R³, R⁴, R⁸ and R⁹ are independently selected from hydrogen,        oxygen, hydroxyl, NH₂, SH, halogen, or a C₁-C₄ organic radical,        and R⁷ and R¹⁰ are independently selected from hydrogen,        hydroxyl, or a C₁-C₄ organic radical, and R⁶ is hydrogen,        halogen, or a C₁-C₄ organic radical;    -   vi) hAr² is a five or six-membered heteroaryl ring having at        least one ring carbon atom and at least one ring nitrogen atom,        and wherein the remaining members of the heteroaryl ring are        independently selected from CR³⁰, N, NR³¹, O, and S, wherein        each R³⁰ is independently selected from hydrogen, hydroxyl, NH₂,        NO₂, SH, SO₃H, P(O)(OH)₂, a halogen, or a C₁-C₄ organic radical,        and each R³¹ is independently selected from hydrogen, or a C₁-C₄        organic radical;        or a comestibly acceptable salt thereof.

In other related embodiments, the compounds of Formula I includecompounds having Formula (IA) shown below that comprise hAr1 radicalsthat are five-membered heteroaryl radicals:

wherein

-   -   i) n′ is zero, one, two, or three, and each R²⁰ is independently        selected from the group consisting of hydroxy, SH, NH₂, a        halogen, or a C₁-C₄ organic radical,    -   ii) n″ is zero, one, two, or three, and each R³⁰ is        independently selected from the group consisting of hydroxy, SH,        NH₂, a halogen, or a C₁-C₄ organic radical,    -   iii) X is NH, O, S, S(O), SO₂, or CH₂,    -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl,        thiofuranyl, pyrrolyl, benzofuranyl, benzothiofliranyl, or        benzopyrrolyl ring    -   v) hAr1 has the structure:

-   -   -   (1) X₁ is NH, O, or S,        -   (2) X₂ is N or CR⁶ wherein R⁶ is hydrogen, a halogen, or a            C₁-C₄ organic radical,        -   (3) X₃ is N or CR⁶ wherein R⁶ is hydrogen, a halogen, or a            C₁-C₄ organic radical, and

    -   vi) hAr² is a pyridyl, pyrazinyl, or pyrimidinyl ring;

or a comestibly acceptable salt thereof.

The genera and subgenera of linked heteroaryl compounds defined abovecomprise many previously unknown subgenuses of compounds, and/or speciesof compounds, and also comprise some compounds that may have beenpreviously reported in the prior art in connection with other uses.Nevertheless, to the knowledge and belief of the Applicants, the priorart has not recognized that the compounds shown above and their variousgenara and subgenera are useful for modifying, improving, and/orenhancing the umami flavor of comestible compositions at theunexpectedly low concentrations disclosed herein.

The Ar Radical and its Substitutents

The Ar radical of the compounds of Formula (I) and its varioussubgenuses can be an optionally substituted monocyclic or bicyclic arylor heteroaryl radicals (as defined elsewhere herein) comprising one ortwo aromatic rings independently selected from benzene rings and five orsix membered heteroaryl rings, with one, two, or three optional R²⁰substitutents which may be attached at any of the positions of the arylor heteroaryl ring radical other than the position which provides thelink to the Y or hAr¹ radical.

In many embodiments of the compounds of Formula I and its subgenera, Aris a monocyclic or bicyclic aryl radical that comprises one at least onebenzene ring. When Ar is a monocyclic aryl, exemplary Ar radicals couldinclude the following structures:

In some embodiments of the compounds of Formula I and its subgenera, Arhas the formula:

If Ar is a bicyclic aryl radical, exemplary Ar radicals could includethe followings structures:

In other embodiments of the compounds of Formula (I) and its subgenera,Ar is an optionally substituted monocyclic or bicyclic heteroarylradical comprising one or two aromatic rings independently selected fromfive or six membered heteroaryl rings. Monocyclic heteroaryl Ar ringswith a six membered ring include optionally substituted pyridyl,pyrazinyl, or pyrimidinyl rings, which include but are not limited tothe following exemplary structures:

Monocyclic heteroaryl Ar rings with a five membered rings includeoptionally substituted furanyl, thiofuranyl, pyrrolyl, pyrazolyl,oxazolyl, or isoxazolyl ring, which include but are not limited to thefollowing exemplary structures:

Bicyclic heteroaryl Ar ring radicals can include optionally substitutedrings such as benzofuranyl, benzothiofuranyl, or benzopyrrolyl radicals,or other heteroaryl radicals such as the following:

In the various embodiments of the compounds of Formula I and its varioussubgenera described herein, the Ar radical can be optionally substitutedwith one, two, or three R²⁰ substituent radicals, wherein each R²⁰radical is independently selected from hydroxyl, NH₂, SH, halogen, or aC₁-C₄ organic radical. Suitable subclasses of the C₁-C₄ organic radicalsinclude alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H,CHO, COR²¹, CO₂R²¹, NHR²¹, NR²¹R²¹′, SR²¹, S(O)R²¹, and SO₂R²¹ radicals,wherein R²¹ and R^(21′) are independently selected alkyls. In someembodiments of the compounds of Formula (I), the R²⁰ and/or R^(20′)radicals are independently selected from hydroxy, fluoro, chloro, NH₂,NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl, isopropyl,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxygroups. In yet additional embodiments, the R²⁰ and/or R^(20′) radicalsare independently selected from methyl, methoxy, and ethyl groups.

In many embodiments of the compounds of Formula (I), it is desirablethat the Ar ring radical have a limited range of overall size andmolecular weight. Accordingly, in some embodiments, the Ar radicalcomprises from 4 to 16 carbon atoms, or from 5 to 12 carbon atoms, orfrom 6 to 10 carbon atoms.

In many embodiments of the compounds of Formula (I), hAr¹ is anoptionally substituted five or six-membered heteroaryl ring radical. ThehAr¹ heteroaryl radicals comprise at least two ring carbon atoms thatform bonds that link the heteroaryl ring of the hAr¹ radical to theother radicals of the compounds of Formula (I). The hAr¹ heteroarylradicals also comprise one to three ring heteroatoms independentlyselected from O, N, or S, and any remaining members of theheteroaromatic ring are independently selected from CR⁶, N, and NR⁷,wherein the R⁶ and R⁷ radicals are further described below. Accordingly,the hAr¹ radicals could have as few as zero and as many as three R⁶ andR⁷ radicals. It is to be understood that all possible substitutionpatterns of the carbon, nitrogen, and sulfur atoms of the heteroarylrings and their optional substituents that are reasonably chemicallystable and are comestibly acceptable are within the scope of theinvention.

The hAr¹ Radical

The hAr¹ radical of the compounds of Formula (I) and its varioussubgenuses is an optionally substituted monocyclic or bicyclicheteroaryl radical (as defined elsewhere herein) comprising one or twofive or six membered heteroaryl rings, with one, two, or three optionalR⁶ or R⁷ substitutents which may be attached at any of the positions ofthe hAr¹ heteroaryl ring radical other than those used to bond hAr¹ tothe Ar and/or Y radicals, and also to the X radical.

In some embodiments of the compounds of Formula (I) and its subgenera,the hAr¹ radicals are an optionally substituted six membered heteroarylradical such as hAr¹ is a pyridyl, pyrazinyl, pyridazinyl, orpyrimidinyl radical having the structure:

wherein the optional R⁶ and R^(6′) substituent radicals can be definedas disclosed below. In many embodiments of the compounds of Formula (I),the pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl radicals areunsubstituted, but may be bonded to the neighboring groups in anygeometry, as illustrated below:

More specifically, the pyridyl, pyrazinyl, pyridazinyl or pyrimidinylradicals include but are not limited to the following exemplarystructures:

In some related embodiments of the compounds of Formula (I) and itssubgenera, the hAr¹ radicals are an optionally substituted five memberedheteroaryl radical such as a furanyl, thiofuranyl, or pyrrolyl radical,which include but are not limited to the following exemplary structures:

In the hAr¹ structures listed above, the R⁶ radicals can be a halogen,or a C₁-C₄ organic radical. Suitable subclasses of the C₁-C₄ organicradicals include alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl,CN, CO₂H, CHO, COR²¹, CO₂R²¹, NHR²¹, NR²¹R²¹′, SR²¹, S(O)R²¹, and SO₂R²¹radicals, wherein R²¹ and R^(21′) are independently selected alkyls. Insome embodiments, R⁶ is hydrogen or a C₁-C₄ alkyl or alkoxyl radical. Insome embodiments, the R⁶ radicals are independently selected fromhydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl,ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy groups. In many embodiments, R⁶ is hydrogen. In thehAr¹ structures listed above, R can be hydrogen or a C₁-C₄ alkylradical, and in many embodiments, R⁷ is hydrogen.

In many embodiments of the compounds of Formula (I), hAr¹ is anoptionally substituted diazole or triazole radical having the structure:

-   -   wherein R⁷ is as is defined above. In many such embodiments, R⁷        is hydrogen or a C₁-C₄ alkyl, or more preferably hydrogen. In        certain preferred embodiments of the compounds of Formula (I),        hAr¹ is an unsubstituted triazole having the structure:

It should be understood that under some conditions of temperature, pH,and other variables, many of the heteroaryl compounds recited hereinthat comprise aromatic NH or OH groups, including the triazole compoundssuch as those listed above can and do tautomerize so as to equilibratethe three structures shown above, and that in these embodiments of thecompounds of Formula (I) a real sample of the compound can and oftendoes comprise the mixture of such tautomers. Accordingly, if only onetautomer is shown in this specification and/or the appended claims, itshould be understood that the other tautomers are within the scope ofsuch a claim unless it is clearly indicated to the contrary.

In other embodiments of the compounds of Formula I and its subgenera,the hAr¹ radical can be a tetrazole radical having the structure:

In some embodiments of the compounds of Formula (I) and its subgenera, ,hAr¹ is an unsubstituted heteroaryl radical having one of the structuresillustrated below:

The hAr2 Radical

In many embodiments of the compounds of Formula (I), hAr² is anoptionally substituted phenyl radical or and optionally substituted fiveor six-membered heteroaryl ring radical that is linked via the X and/orone or more CR³R⁴ groups to the hAr¹ radical described above.

In some embodiments of analogs of the compounds of Formula I, hAr² is aphenyl ring optionally substituted with 0, 1, 2, or 3 R³⁰ radicalsindependently selected from hydrogen, a halogen, or a C₁-C₄ organicradical. In some embodiments of the compounds of Formula I, the hAr2radical is a heteroaryl radical as that term in defined elsewhereherein, and the hAr² heteroaryl radical has at least one ring carbonatom that is bonded to the X and optional CR³R⁴ groups, and at least oneadditional ring carbon atom, and at least one ring nitrogen atom. Theremaining ring members of the five or six membered heteroaryl ring canbe independently selected from CR³⁰, N, NR³¹, O, and S, so long as thevalences of the CR³⁰, N, NR³¹, O, and S radicals are selected in acombination that results in the formation of a fully conjugated aromaticand delocalized heteroaryl ring having 4n+2 “π” electrons, a selectionand/or condition that can be readily ascertained by those of ordinaryskill in the art of organic chemistry.

In such embodiments of hAr², each R³⁰ can be independently selected fromhydrogen, a halogen, or a C₁-C₄ organic radical and each R³¹ can beindependently selected from hydrogen, or a C₁-C₄ organic radical.Suitable subclasses of the C₁-C₄ organic radicals include alkyl,alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR²¹,CO₂R²¹, NHR²¹, NR²¹R²¹′, SR²¹, S(O)R²¹, and SO₂R²¹ radicals, wherein R²¹and R^(21′) are independently selected alkyls. In some embodiments, eachR³⁰ is independently selected from hydrogen or a C₁-C₄ alkyl or alkoxylradical. In some embodiments, each R³⁰ radical can be independentlyselected from hydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt,SCH₃, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy groups. In some embodiments, each R³⁰is group is hydrogen. In the hAr² structures listed above, R³¹ can behydrogen or a C₁-C₄ alkyl radical, and in many embodiments, R³⁰ ishydrogen.

In some embodiments of the invention, hAr² is a five membered heteroarylradical having one of the exemplary structures shown below:

In many preferred embodiments of the invention, hAr² is a six memberedheteroaryl radical such as a pyridyl, pyrazinyl, or pyrimidinyl radical,wherein the optional R³⁰ radicals are independently selected fromhydroxy, SH, NH₂, a halogen an alkyl, alkoxyl, alkoxy-alkyl,hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR³², CO₂R³² , NHR³², NR³²R³²′or SR³² radical, wherein R³² and R32′ are independently selected alkyls.Exemplary structures for the pyridyl, pyrazinyl, or pyrimidinyl radicalsare shown below:

In certain preferred embodiments, hAr² is a 2-pyridyl, 2-pyrazinyl, or2-pyrimidinyl radical, as shown below:

In some embodiments, each R³⁰ and/or R^(30′) radical of the hAr² radicalis independently selected from hydroxy, fluoro, chloro, NH₂, NHCH₃,N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl, isopropyl, trifluoromethyl,methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In manyembodiments, each R³⁰ is hydrogen (i.e. n″ is zero).

In many preferred embodiments, hAr² is an unsubstituted 2-pyridylradical, as shown below:

The Linker Groups X, Y, and (CR₃R₄)

As stated above, the hAr¹, hAr² and Ar ring groups can be linkedtogether by bridging or linking groups X, Y, and/or CR₃R₄ as will now befurther described. The Ar and hAr¹ groups can be optionally linked (whenm=1) by a divalent “Y” atom or group that bridges Ar and hAr¹. The Ygroup generally consists of an atom with one bond to the Ar ring andanother bond to the hAr¹ radical, and optionally other substituentgroups, and can have many structures that include but are not limited toO, S, S(O), SO₂, CR¹R², or NR⁵, so as to form compounds of Formula (I)having the following structures:

Alternatively, in many embodiments of the compounds of the invention,m=0, so that the Y group is absent and the Ar and hAr¹ rings aredirectly bonded/linked to each other as shown below:

Unlike the “Y” group, the “X” group is typically present in thecompounds of Formula (I), a nd is bonded to the hAr¹ group, and at leastforms a bond or a link to the CR³R⁴ and/or hAr² heteroaryl ring group.Again, the X group generally comprises of a divalent atom or group withone bond to the hAr¹ ring and another bond to the CR³R⁴ and/or hAr²heteroaryl ring groups, and optionally other substituent groups, so asto form a link or bridge between hAr¹ and CR³R⁴ and/or hAr² heteroarylring groups. The X group can have many structures that include but arenot limited to O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰, so as to form compoundsof Formula (I) having the following structures:

In some embodiments, is X is S, NH, or O, and in many preferredembodiments, X is S.

Lastly, the CR³R⁴ groups are optional (i.e. n can be zero, one, two, orthree) bridging groups that are bonded to the X group and bond or linkit to the hAr² heteroaryl ring. It is to be understood that unless thereis a clear and contrary indication in the claims, if there is more thanone CR³R⁴ group in a given molecule, the R³ and R⁴ substitutents can beindependently chosen for each CR³R⁴ group present. In some embodiments,n is two, and would result in compounds having the following structure:

In many embodiments, n is one, so as to produce a subgenus of thecompounds of Formula (I) having the structure:

In many embodiments, m is zero and n is one, so as to produce a subgenusof the compounds of Formula (I) having the structure:

In the foregoing discussion, certain R¹-R¹⁰ substituent groups have beendefined in connection with other features of the linked heteroarylcompounds of Formula (I). In general, each of substitutent groups can beselected independently from the other groups. More specifically R¹, R²,R³, R⁴, R⁸ and R⁹ can be independently selected from inorganic radicalsor groups that include hydrogen, oxygen, hydroxyl, NH₂, SH, or a halogen(fluorine, chlorine, bromine, or iodine), or a C₁-C₄ organic radical. R⁷and R¹⁰ can be independently selected from hydrogen, hydroxyl, or aC₁-C₄ organic radical, and R⁶ can be hydrogen, halogen, or a C₁-C₄organic radical. Suitable C₁-C₄ organic radicals include but are notlimited to certain subgenuses of organic radicals such as an alkyl,alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR^(x),CO₂R^(x), NHR^(x), NR^(x)R^(x′), SR^(x), S(O)R^(x), and SO₂R^(x) whereinR^(x) is an alkyl. In some embodiments, the C₁-C₄ organic radicals areselected from NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl,isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy groups. In many embodiments, one or all of R¹-R¹⁰ arehydrogen.

In certain preferred embodiments of the linked heteroaryl compounds ofFormula (I), m=0 (i.e. the Y group is absent), n=1 and the R³ and R⁴groups are hydrogen so as to form a single methylene group that linksthe X and hAr² rings, and Ar, hAr¹ and hAr² are limited to certainpreferred aromatic ring systems, to form a preferred subgenus of linkedheteroaryl compound having Formula (IA) as shown below:

-   -   wherein        -   i) n′ is zero, one, two, or three, and each R₂₀ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   ii) n″ is zero, one, two, or three, and each R₃₀ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   iii) X is NH, O, S, S(O), SO₂, or CH₂,        -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl,            furanyl, thiofuranyl, pyrrolyl, benzofuranyl,            benzothiofuranyl, or benzopyrrolyl ring        -   v) hAr¹ has the structure

-   -   -   -   (1) X₁ is NH, O, or S,            -   (2) X₂ is N or CR⁶ wherein R⁶ is hydrogen, a halogen, or                a C₁-C₄ organic radical,            -   (3) X₃ is N or CR⁶ wherein R⁶ is hydrogen, a halogen, or                a C₁-C₄ organic radical, and

        -   vi) hAr² is a pyridyl, pyrazinyl, or pyrimidinyl ring.

As is apparent from the disclosure of the compounds of Formula (IA)above, the hAr¹ ring radical a subgenus of five-membered heteroaryls, asdefined by the selection/identity of the X₁, X₂, and X₃ atoms, radicals,or groups. In certain narrower subgenuses, X₁ is NH. In other narrowersubgenuses, X₂ can be N or CH, while X₃ is independently N or CH. Insome preferred subgenuses, X₂ and X₃ are N.

In other preferred subgenuses, X₁ is NH, and X₂ and X₃ are N, so thatthe resulting hAr¹ ring is a triazole ring radical having the structureshown below:

-   -   wherein it is to be recognized that tautomerism may, at least        under some conditions, result in a mixture of the three triazole        groups in the compounds of Formula (IA).

Additionally, in some embodiments of the compounds of Formula (IA), Aris preferably a phenyl or furanyl radical, and the X group is S, NH, orO, or more preferably S or O. In some preferred embodiments of thecompounds of Formula (IA), hAr² is a 2-pyridinyl radical having thestructure:

-   -   wherein n″ is preferably 1 or 0.

In many embodiments of the compounds of Formula (IA), the R²⁰ and/or R³⁰radicals are independently selected from hydroxy, SH, NH₂, a halogen,alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO,COR^(x), CO₂R^(x), NHR^(x), NR^(x)R^(x′), or SR^(x) radical, whereinR^(x) is an alkyl, or even more preferably, the R²⁰ and/or R³⁰ radicalsare independently selected from the group consisting of a hydroxy,fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl,isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy group.

Another preferred subgenus of the compounds of Formula (I) are thetriazole compounds of Formula (IB) shown below:

-   -   wherein        -   i) n′ is zero, one, two, or three, and each R²⁰ is            independently selected from hydroxy, SH, NH₂, a halogen, and            a C₁-C₄ radical selected from an alkyl, alkoxyl,            alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR²¹,            CO₂R²¹, NHR²¹, NR²¹R^(21′), or SR²¹ radical, wherein R²¹ and            R^(21′) is an alkyl,        -   ii) n″ is zero, one, two, or three, and each R³⁰ is            independently selected from hydroxy, SH, NH₂, a halogen, and            a C₁-C₄ radical selected from an alkyl, alkoxyl,            alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR³²,            CO₂R³², or SR³² radical, wherein R³² and R^(32′) is an            alkyl,        -   iii) X is NH, O, S, S(O), SO₂, or CH₂,        -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl,            furanyl, thiofuranyl, or pyrrolyl ring,    -   or a comestibly acceptable salt thereof.

In yet other embodiments, the invention relates to a subgenus of thecompounds of Formula (I) wherein hAr¹ is a triazole ring, but both the Xand Y linker groups are present, as illustrated by the compounds ofFormula (IC) shown below:

-   -   wherein        -   i) n′ is zero, one, two, or three, and each R²⁰ is            independently selected from the group consisting of            hydroxyl, SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   ii) n″ is zero, one, two, or three, and each R³⁰ is            independently selected from the group consisting of OH, SH,            NH₂, a halogen, or a C₁-C₄ organic radical,        -   iii) X is NH, O, S, S(O), SO₂, or CR⁸R⁹, wherein R⁸ and R⁹            are independently selected from hydrogen, oxygen, hydroxyl,            NH₂, a halogen, or a C₁-C₄ organic radical,        -   iv) Y is NH, O, S, S(O), SO₂, or CR⁸R⁹, wherein R⁸ and R⁹            are independently selected from hydrogen, oxygen, hydroxyl,            NH₂, a halogen, or a C₁-C₄ organic radical,        -   v) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl,            thiofuranyl, or pyrrolyl ring,    -   or a comestibly acceptable salt thereof.

In additional embodiments, the invention relates to a subgenus of thecompounds of Formula (I) wherein hAr¹ is a six membered heteroarylcomprising one or two nitrogen atoms, as illustrated by the compounds ofFormula (ID) shown below:

-   -   and wherein        -   i) n′ is zero, one, two, or three, and each R²⁰ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   ii) n″ is zero, one, two, or three, and each R³⁰ is            independently selected from the group consisting of hydroxy,            SH, NH₂, a halogen, or a C₁-C₄ organic radical,        -   iii) X is NH, O, S, S(O), SO₂, or CH₂,        -   iv) Ar is a phenyl, pyridyl, pyrazinyl, pyrimidinyl,            furanyl, thiofuranyl, pyrrolyl, benzofuranyl,            benzothiofuranyl, or benzopyrrolyl ring        -   v) hAr¹ has the structure:

-   -   -    wherein R⁶ and R^(6′) are independently selected from            hydrogen, a halogen, or a C₁-C₄ organic radical, and        -   vi) hAr² is a pyridyl, pyrazinyl, or pyrimidinyl ring.

In some embodiments of the compounds Formula (ID), Ar is a phenyl ring,n′ is one or two, and each R₂₀ is independently selected from the groupconsisting of methyl, ethyl, isopropyl, trifluoromethyl, methoxy,trifluoromethoxy, and ethoxy. In other embodiments of the compoundsFormula (ID), Ar is a phenyl ring comprising an alkylene dioxy ringfused thereto, such as Ar groups having the structure:

In some embodiments of the compounds Formula (ID), Ar is a furanyl ring,n′ is one or two, and each R₂₀ is independently selected from the groupconsisting of methyl, ethyl, isopropyl, trifluoromethyl, methoxy,trifluoromethoxy, and ethoxy.

In some embodiments of the compounds Formula (ID), hAr¹ is anunsubstituted pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl radicalhaving the structure:

In some embodiments of the compounds of Formula (ID), hAr² is anoptionally substituted pyridyl radical having the structure:

-   -   wherein each R₃₀, if present, is independently selected from the        group consisting of a hydroxy, fluoro, chloro, NH₂, NHCH₃,        N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl, isopropyl,        trifluoromethyl, methoxy, ethoxy, isopropoxy, and        trifluoromethoxy. Preferably, the pyridinyl radical is a        2-pyridinyl radical having the structure:

-   -   wherein n″ is 0 or 1, and more preferably n″ is 0.

In many embodiments of the compounds of Formula (I) and its subgenuses(IA), (IB), (IC), and (ID) disclosed above, the linked heteroarylcompounds are preferably formulated as “small molecules” as compared tomany biological molecules, and can have a variety of limitations ontheir overall absolute physical size, molecular weight, and physicalcharacteristics, so that they can be at least somewhat soluble inaqueous media, and are of appropriate size to effectively bind to therelevant heterodimeric T1R1/T1R3 taste receptors.

Therefore, in many embodiments of the compounds of Formula (I) and/orits various subgenuses, the molecular weight of the compounds of Formula(I) should be less than about 800 grams per mole, or in further relatedembodiments less than or equal to about 700 grams per mole, 600 gramsper mole, 500 grams per mole, 450 grams per mole, 400 grams per mole,350 grams per mole, or 300 grams per mole. Similarly, the compounds ofFormula (I) can have preferred ranges of molecular weight, such as forexample from about 175 to about 500 grams per mole, from about 200 toabout 450 grams per mole, from about 225 to about 400 grams per mole,from about 250 to about 350 grams per mole.

The molecular weight and/or hydrophilic character of the compounds canalso be modified by placing limits on the number of carbon atoms in thecompounds of the invention. Accordingly, in some embodiments, thecompounds of Formula (I) have between 10 and 22 carbon atoms, oralternatively between 12 and 20 carbon atoms.

Moreover, it is desirable that the compounds of Formula (I) and itssubgenuses and species have sufficient polarity and/or polar functionalgroups so that they are at least somewhat soluble in aqueous biologicalfluids, such as saliva. A well known indicator of such water solubilityis the log¹⁰ of the partition coefficient of a given compound betweenn-octanol and water, a parameter which can be readily and quicklyestimated by computer-based calculations from the structure of thecompound by many modern chemical software packages, so that “designing”compounds with sufficient estimated water solubility does not in thismodern age typically require actual synthesis of the compounds, thoughexperimental confirmation of the water solubility of the compounds isdesirable once promising candidate compounds have been synthesized.Accordingly, in some embodiments of the invention, the log¹⁰ of thepartition coefficient of the compound between n-octanol and water isless than 5.5, preferably less than 5.0, or less than 4.5.

For the various embodiments and/or subgenuses of the compounds ofFormula (I), it is hereby specifically contemplated that any ofsubgenuses and/or species of compounds of Formula (I) described belowcan, either in their specified form or as a comestibly acceptable salt,be combined in an effective amount with a comestible product orprecursor thereof by the processes and/or methods described elsewhereherein, or by any such other processes as would be apparent to those ofordinary skill in preparing comestible or medicinal products orprecursor thereof, to form a savory flavor modified comestible product,or a precursor thereof.

Comestibly Acceptable Compounds, Salts thereof, and/or ComestibleCompositions

Many of the linked heteroaryl compounds of Formula (I) or its variousenumerated subgenuses comprise acidic or basic groups, with the resultthat those acidic or basic groups can be neutralized by correspondingcommestibly acceptable acids or bases to form comestibly acceptablesalts, and the compounds of Formula (I) can be administered in the formof the comestibly acceptable salts, many of which have been recognizedas GRAS (generally recognized as safe).

Additionally, depending on the acidic or basic character (“pH”) of thecomestible compositions in which the compounds of Formula (I) areformulated, they may be present as salts which preferably are comestiblyacceptable salts. The compounds of Formula (I) having acidic substituentgroups, such as carboxylic acids, will tend (at near neutralphysiological pH) to be present in solution in the form of anioniccarboxylates, and therefore will in preferred embodiments have anassociated comestibly and/or pharmaceutically acceptable cation, many ofwhich are known to those of ordinary skill in the art. Such comestiblyacceptable cations include alkali metal cations (lithium, sodium, andpotassium cations), alkaline earth metal cations (magnesium, calcium,and the like), or ammonium (NH₄)⁺ or organically substituted ammoniumcations such as (R—NH₃)⁺ cations.

The compounds of Formula (I) having basic substituent groups, such asamino groups or heterocyclic rings comprising nitrogen atoms, will tend(at near neutral physiological pH, or at the acidic pH common in manyfoods) to be actually present in solution in the form of cationicammonium groups, and therefore will in preferred embodiments have anassociated comestibly acceptable anion, many of which are known to thoseof ordinary skill in the art. Such comestibly acceptable anionic groupsinclude the anionic form of a variety of carboxylic acids (acetates,citrates, tartrates, anionic salts of fatty acids, etc.), halides(especially fluorides or chlorides), nitrates, phosphates, sulfates, andthe like.

The linked heteroaryl compounds of Formula (I) and its varioussubgenuses, and their salts, should preferably be comestibly acceptable,i.e. deemed suitable for consumption in food or drink from theperspective of giving unmodified comestible compositions an improvedand/or pleasing savory taste, and would not be significantly toxic orcauses unpleasant or undesirable pharmacological or toxicologicaleffects on an animal or human at the typically low concentrations theyare employed as flavoring agents for the comestible compositions.

The typical method of demonstrating that a flavorant compound iscomestibly acceptable is to have the compound tested and/or evaluated byan Expert Panel of the Flavor and Extract Manufacturers Association anddeclared as to be “Generally Recognized As Safe” (“GRAS”). The FEMA/GRASevaluation process for flavorant compounds is complex but well known tothose of ordinary skill in the food product preparation arts, as isdiscussed by Smith, et al. in an article entitled “GRAS FlavoringSubstances 21,” Food Technology, 57(5), pgs 46-59, May 2003, the entirecontents of which are hereby incorporated herein by reference.

When being evaluated in the FEMA/GRAS process, a new flavorant compoundis typically tested for any adverse toxic effects on laboratory ratswhen fed to such rats for at least about 90 days at a concentration atleast 100-fold higher, or 1000-fold, or higher concentrations than theproposed maximum allowable concentration of the compound in a particularcategory of food products being considered for approval. For example,such testing of the compounds of Formula (I) might involve combining thecompound with rat chow and feeding it to laboratory rats such asCrl:CD(SD)IGS BR rats, at a concentration of about 100milligrams/kilogram body weight/day for 90 days, and then sacrificingand evaluating the rats, and using various known medical testingprocedures to show that the compound of Formula (I) causes no adversetoxic effects on the rats.

The compounds of Formula (I) are not, at least in most embodiments,currently known to have independent pharmaceutical or biologicalactivity for the treatment of diseases in animals or humans, or intendedto be administered or marketed as pharmaceutically active agents. Thelinked heteroaryl compounds of Formula (I) and its various subgenusesmight nevertheless, in some embodiments, be used and marketed asflavorants to modify or improve the taste of certain types of“pharmaceutical” or “nutraceutical” compositions, such as vitaminenriched comestible compositions, such as soups, and in many suchembodiments the compounds of the present invention would often beformulated in combination with MSG or other savory tastant compounds, inorder to enhance the savory flavor of such neutraceutical compositions.

In view of the discussion above, if it has already been discovered or islater discovered that one or more of the compounds of Formula (I) or apharmaceutical composition thereof is known and/or has pharmaceutical orbiological activity for the treatment of diseases, then in connectionwith claims to methods of modifying the savory taste of comestiblecompositions that encompass the use of such known compounds, and inconnection with claims to comestible compositions derived from theaforementioned methods, additional embodiments of such methods orcomestible compositions in connection with the current invention caninclude a recitation that the methods and compositions claimed hereinmust also comprise MSG.

The Compounds of the Invention as Savory Taste Enhancers

The linked heteroaryl compounds of Formula (I) and its various compoundsub-genuses and species, as described above are intended to be savoryflavorant compounds or flavor modifiers for comestible products. As isapparent from the teachings and Examples herein, many compounds ofFormula (I) are agonists of an hT1R1/hT1R3 “savory” receptor, at leastat concentrations of about 100 μM or less. Accordingly many of the amidecompounds of Formula (I) have a significant savory flavor independent ofthe presence or absence of MSG, and therefore can have utility asindependent savory flavorants or flavor enhancers.

Nevertheless, it is preferable to use as little of such artificialflavorants as possible, so as to minimize both cost and any undesirablehealth side effects of administration of the compounds of Formula (I) athigh concentration levels. Accordingly, it is desirable to test thecompounds of Formula (I) for their effectiveness as taste receptoragonists at lower concentration levels, so as to identify the best andmost effective linked heteroaryl compounds of Formula (I). As wasdisclosed in WO 03/001876, and U.S. Patent Publication US 2003-0232407A1, hereby incorporated herein by reference and as describedhereinbelow, laboratory procedures now exist for measuring the agonistactivities of compounds for an hT1R1/hT1R3 “savory” receptor. Suchmeasurement methods typically measure an “EC₅₀”, i.e. the concentrationat which the compound causes 50% activation of the relevant receptor.

Preferably, the linked heteroaryl compounds of Formula (I) that aresavory flavor modifiers have an EC₅₀ for the hT1R1/hTIR3 receptor ofless than about 10 μM. More preferably, such compounds have an EC₅₀ forthe hT1R1/hT1R3 receptor of less than about 5 μM, 3 μM, 2 μM, 1 μM, or0.5 μM.

In some embodiments, the compounds of Formula (I) are savory flavormodulators or enhancers of the agonist activity of monosodium glutamatefor an hT1R1/hT1R3 receptor. Hereinbelow is described an assay procedurefor so-called EC₅₀ ratios, i.e. for dissolving a compound of Formula (I)in water containing MSG, and measuring the degree to which the amidecompound lowers the amount of MSG required to activate 50% of theavailable hT1R1/hTIR3 receptors. Preferably, the compounds of Formula(I), when dissolved in an aqueous solution comprising about 1 μM of thelinked heteroaryl compound will decrease the observed EC₅₀ of monosodiumglutamate for an hT1R1/hT1R3 receptor expressed in an HEK293-Gα15 cellline by at least 50%, i.e. the compound will have an EC50 ratio of atleast 2.0, or preferably 3.0, 5.0, or 7.0.

The above identified assays are useful in identifying the most potent ofthe compounds of Formula (I) for savory taste modifier or enhancerproperties, and the results of such assays are believed to correlatewell with actual savory taste perception in animals and humans, butultimately the results of the assays can be confirmed, at least for themost potent of the compounds of Formula (I), by human taste testing.Such human taste testing experiments can be well quantified andcontrolled by tasting the candidate compounds in aqueous solutions, ascompared to control aqueous solution, or alternatively by tasting thecompounds of the inventions in actual food compositions.

Accordingly, in order to identify the more potent of the savory tastemodifiers or agents, a water solution comprising a savory flavormodifying amount of any particular linked heteroaryl compound of Formula(I) or one of its subgenuses should have a savory taste as judged by themajority of a panel of at least eight human taste testers.

Correspondingly, in order to identify the more potent of the savorytaste enhancers, a water solution, comprising a savory flavor modifyingamount of a compound of Formula (I) and 12 mM monosodium glutamate,would have an increased savory taste as compared to a control watersolution comprising 12 mM monosodium glutamate, as determined by themajority of a panel of at least eight human taste testers. Preferably,in order to identify the more potent of the savory taste enhancers, awater solution comprising a savory flavor modifying amount (preferablyabout 30, 10, 5, or 2 ppm) of the compound of Formula (I) and 12 mMmonosodium glutamate will have an increased savory taste as compared toa control water solution comprising 12 mM monosodium glutamate and 100μM inosine monophosphate, as determined by the majority of a panel of atleast eight human taste testers.

Using the Compounds of Formula (I) to Prepare Comestible Compositions

Flavors, flavor modifiers, flavoring agents, flavor enhancers, savory(“umami”) flavoring agents and/or flavor enhancers, prepared from thecompounds of Formula I and its various subgenera and species compoundsherein, and their commestibly acceptable salts, and compositionsthereof, have application in foods, beverages and other comestiblecompositions wherein savory compounds, especially MSG, IMP, or GMP areconventionally utilized. These compositions include compositions forhuman and animal consumption. This includes food or drinks (liquids) forconsumption by agricultural animals, pets and zoo animals.

Those of ordinary skill in the art of preparing and selling comestiblecompositions (i.e edible foods or beverages, or precursors or flavormodifiers thereof) are well aware of a large variety of classes,subclasses and species of the comestible compositions, and utilizewell-known and recognized terms of art to refer to those comestiblecompositions while endeavoring to prepare and sell various of thosecomestible compositions. Such a list of terms of art is enumeratedbelow, and it is specifically contemplated hereby that the varioussubgenuses and species of the compounds of Formula (I) could be used tomodify or enhance the savory flavors of the following list comestiblecompositions, either singly or in all reasonable combinations ormixtures thereof:

-   -   One or more confectioneries, chocolate confectionery, tablets,        countlines, bagged selflines/softlines, boxed assortments,        standard boxed assortments, twist wrapped miniatures, seasonal        chocolate, chocolate with toys, alfajores, other chocolate        confectionery, mints, standard mints, power mints, boiled        sweets, pastilles, gums, jellies and chews, toffees, caramels        and nougat, medicated confectionery, lollipops, liquorice, other        sugar confectionery, gum, chewing gum, sugarised gum, sugar-free        gum, functional gum, bubble gum, bread, packaged/industrial        bread, unpackaged/artisanal bread, pastries, cakes,        packaged/industrial cakes, unpackaged/artisanal cakes, cookies,        chocolate coated biscuits, sandwich biscuits, filled biscuits,        savoury biscuits and crackers, bread substitutes, breakfast        cereals, rte cereals, family breakfast cereals, flakes, muesli,        other rte cereals, children's breakfast cereals, hot cereals,        ice cream, impulse ice cream, single portion dairy ice cream,        single portion water ice cream, multi-pack dairy ice cream,        multi-pack water ice cream, take-home ice cream, take-home dairy        ice cream, ice cream desserts, bulk ice cream, take-home water        ice cream, frozen yoghurt, artisanal ice cream, dairy products,        milk, fresh/pasteurised milk, full fat fresh/pasteurised milk,        semi skimmed fresh/pasteurised milk, long-life/uht milk, fill        fat long life/uht milk, semi skimmed long life/uht milk,        fat-free long life/uht milk, goat milk, condensed/evaporated        milk, plain condensed/evaporated milk, flavoured, finctional and        other condensed milk, flavoured milk drinks, dairy only        flavoured milk drinks, flavoured milk drinks with fruit juice,        soy milk, sour milk drinks, fermented dairy drinks, coffee        whiteners, powder milk, flavoured powder milk drinks, cream,        cheese, processed cheese, spreadable processed cheese,        unspreadable processed cheese, unprocessed cheese, spreadable        unprocessed cheese, hard cheese, packaged hard cheese,        unpackaged hard cheese, yoghurt, plain/natural yoghurt,        flavoured yoghurt, fruited yoghurt, probiotic yoghurt, drinking        yoghurt, regular drinking yoghurt, probiotic drinking yoghurt,        chilled and shelf-stable desserts, dairy-based desserts,        soy-based desserts, chilled snacks, fromage frais and quark,        plain fromage frais and quark, flavoured fromage frais and        quark, savoury fromage frais and quark, sweet and savoury        snacks, fruit snacks, chips/crisps, extruded snacks,        tortilla/corn chips, popcorn, pretzels, nuts, other sweet and        savoury snacks, snack bars, granola bars, breakfast bars, energy        bars, fruit bars, other snack bars, meal replacement products,        slimming products, convalescence drinks, ready meals, canned        ready meals, frozen ready meals, dried ready meals, chilled        ready meals, dinner mixes, frozen pizza, chilled pizza, soup,        canned soup, dehydrated soup, instant soup, chilled soup, uht        soup, frozen soup, pasta, canned pasta, dried pasta,        chilled/fresh pasta, noodles, plain noodles, instant noodles,        cups/bowl instant noodles, pouch instant noodles, chilled        noodles, snack noodles, canned food, canned meat and meat        products, canned fish/seafood, canned vegetables, canned        tomatoes, canned beans, canned fruit, canned ready meals, canned        soup, canned pasta, other canned foods, frozen food, frozen        processed red meat, frozen processed poultry, frozen processed        fish/seafood, frozen processed vegetables, frozen meat        substitutes, frozen potatoes, oven baked potato chips, other        oven baked potato products, non-oven frozen potatoes, frozen        bakery products, frozen desserts, frozen ready meals, frozen        pizza, frozen soup, frozen noodles, other frozen food, dried        food, dessert mixes, dried ready meals, dehydrated soup, instant        soup, dried pasta, plain noodles, instant noodles, cups/bowl        instant noodles, pouch instant noodles, chilled food, chilled        processed meats, chilled fish/seafood products, chilled        processed fish, chilled coated fish, chilled smoked fish,        chilled lunch kit, chilled ready meals, chilled pizza, chilled        soup, chilled/fresh pasta, chilled noodles, oils and fats, olive        oil, vegetable and Seed oil, cooking fats, butter, margarine,        spreadable oils and fats, functional spreadable oils and fats,        sauces, dressings and condiments, tomato pastes and purees,        bouillon/stock cubes, stock cubes, gravy granules, liquid stocks        and fonds, herbs and spices, fermented sauces, soy based sauces,        pasta sauces, wet sauces, dry sauces/powder mixes, ketchup,        mayonnaise, regular mayonnaise, mustard, salad dressings,        regular salad dressings, low fat salad dressings, vinaigrettes,        dips, pickled products, other sauces, dressings and condiments,        baby food, milk formula, standard milk formula, follow-on milk        formula, toddler milk formula, hypoallergenic milk formula,        prepared baby food, dried baby food, other baby food, spreads,        jams and preserves, honey, chocolate spreads, nut-based spreads,        and yeast-based spreads.

Preferably, the compounds of Formula (I) can be used to modify orenhance the savory flavor of one or more of the following sub-genuses ofcomestible compositions: confectioneries, bakery products, ice creams,dairy products, savory snacks, snack bars, meal replacement products,ready meals, soups, pastas, noodles, canned foods, frozen foods, driedfoods, chilled foods, oils and fats, baby foods, or spreads, or amixture thereof.

In general an ingestible composition will be produced that contains asufficient amount of at least one compound within the scope of Formula(I) or its various subgenuses described hereinabove to produce acomposition having the desired flavor or taste characteristics such as“savory” taste characteristics.

Typically at least a savory flavor modulating amount, of one or more ofthe compounds of Formula (I) will be added to the comestible product, sothat the savory flavor modified comestible product has an increasedsavory taste as compared to the comestible product prepared without thecompound of Formula (I), as judged by human beings or animals ingeneral, or in the case of formulations testing, as judged by a majorityof a panel of at least eight human taste testers, via proceduresdescribed elsewhere herein.

The concentration of savory flavoring agent needed to modulate orimprove the flavor of the comestible product or composition will ofcourse vary dependent on many variables, including the specific type ofingestible composition, what savory compounds are already present andthe concentrations thereof, the amount of MSG already present, and theenhancer effect of the particular compound on such savory compounds. Asnoted, a significant application of the compounds of Formula (I) is formodulating (inducing, enhancing or inhibiting) the savory tastes orother taste properties of other natural or synthetic savory tastants,especially MSG. A broad range of concentrations of the compounds ofFormula (I) can be employed to provide such savory taste enhancement,i.e. from about 0.001 ppm to 100 ppm, or narrower alternative rangesfrom about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about 30 ppm,from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm,or from about 0.1 ppm to about 3 ppm.

Examples of foods and beverages wherein compounds according to theinvention may be incorporated included by way of example the Wet SoupCategory, the Dehydrated and Culinary Food Category, the BeverageCategory, the Frozen Food Category, the Snack Food Category, andseasonings or seasoning blends.

“Wet Soup Category” means wet/liquid soups regardless of concentrationor container, including frozen Soups. For the purpose of this definitionsoup(s) means a food prepared from meat, poultry, fish, vegetables,grains, fruit and other ingredients, cooked in a liquid which mayinclude visible pieces of some or all of these ingredients. It may beclear (as a broth) or thick (as a chowder), smooth, pureed or chunky,ready-to-serve, semi-condensed or condensed and may be served hot orcold, as a first course or as the main course of a meal or as a betweenmeal snack (sipped like a beverage). Soup may be used as an ingredientfor preparing other meal components and may range from broths (consomme)to sauces (cream or cheese-based soups). “Dehydrated and Culinary FoodCategory” means: (i) Cooking aid products such as: powders, granules,pastes, concentrated liquid products, including concentrated bouillon,bouillon and bouillon like products in pressed cubes, tablets or powderor granulated form, which are sold separately as a finished product oras an ingredient within a product, sauces and recipe mixes (regardlessof technology); (ii) Meal solutions products such as: dehydrated andfreeze dried soups, including dehydrated soup mixes, dehydrated instantsoups, dehydrated ready-to-cook soups, dehydrated or ambientpreparations of ready-made dishes, meals and single serve entreesincluding pasta, potato and rice dishes; and (iii) Meal embellishmentproducts such as: condiments, marinades, salad dressings, saladtoppings, dips, breading, batter mixes, shelf stable spreads, barbecuesauces, liquid recipe mixes, concentrates, sauces or sauce mixes,including recipe mixes for salad, sold as a finished product or as aningredient within a product, whether dehydrated, liquid or frozen.

“Beverage Category” means beverages, beverage mixes and concentrates,including but not limited to, alcoholic and non-alcoholic ready to drinkand dry powdered beverages.

Other examples of foods and beverages wherein compounds according to theinvention may be incorporated included by way of example carbonated andnon-carbonated beverages, e.g., sodas, fruit or vegetable juices,alcoholic and non-alcoholic beverages, confectionary products, e.g.,cakes, cookies, pies, candies, chewing gums, gelatins, ice creams,sorbets, puddings, jams, jellies, salad dressings, and other condiments,cereal, and other breakfast foods, canned fruits and fruit sauces andthe like.

Additionally, the subject compounds can be used in flavor preparationsto be added to foods and beverages. In preferred instances thecomposition will comprise another flavor or taste modifier such as asavory tastant.

Accordingly, in some embodiments, the inventions relate to methods formodulating the savory taste of a comestible product comprising:

a) providing at least one comestible product, or a precursor thereof,and

-   -   i. combining the comestible product or precursor thereof with at        least a savory flavor modulating amount of at least one compound        of Formula (I) or any of its subgenuses, or a comestibly        acceptable salt thereof, so as to form a modified comestible        product.

The invention also relates to the modified comestible products producedby such processes, and similar processes for producing comestibleproducts well known to those of ordinary skill in the art, especially ifsuch compositions comprise MSG, and the compound is employed as a savorytaste enhancer for the MSG also present in the composition.

The amide compounds of Formula (I) and its various subgenuses can becombined with or applied to the comestible or medicinal products orprecursor thereof in any of innumerable ways known to cooks the worldover, or producers of comestible or medicinal products. For example, thecompounds of Formula (I) could be dissolved in or dispersed in or one ofmany known comestibly acceptable liquids, solids, or other carriers,such as water at neutral, acidic, or basic pH, fruit or vegetablejuices, vinegar, marinades, beer, wine, natural water/fat emulsions suchas milk or condensed milk, edible oils and shortenings, fatty acids,certain low molecular weight oligomers of propylene glycol, glycerylesters of fatty acids, and dispersions or emulsions of such hydrophobicsubstances in aqueous media, salts such as sodium chloride, vegetableflours, solvents such as ethanol, solid edible diluents such asvegetable powders or flours, and the like, and then combined withprecursors of the comestible or medicinal products, or applied directlyto the comestible or medicinal products.

Making the Linked Heteroaryl Compounds of Formula (I)

The starting materials used in preparing the compounds of the invention,i.e. the various structural subclasses and species of the compounds ofthe synthetic precursors of the linked heteroaryl compounds of Formula(I), especially the organic carboxylic acids and benzoic acids,isocyanates, and the various amines, anilines, amino acids, etc., areoften known compounds, or can be synthesized by known methods describedin the literature, or are commercially available from various sourceswell known to those of ordinary skill in the art, such as for example,Sigma-Aldrich Corporation of St. Louis, Mo. USA and their subsidiariesFluka and Riedel-de Haën, at their various other worldwide offices, andother well known chemical suppliers such as Fisher Scientific, TCIAmerica of Philadelphia, Pa., ChemDiv of San Diego, Calif., Chembridgeof San Diego, Calif., Asinex of Moscow, Russia, SPECS/BIOSPECS of theNetherlands, Maybridge of Cornwall, England, Acros, TimTec of Russia,Comgenex of South San Francisco, Calif., and ASDI Biosciences of Newark,Del.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out the synthesis of many starting materialsand subsequent manipulations without further direction, that is, it iswell within the scope and practice of the skilled artisan to carry outmany desired manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification, saponification, nitrations,hydrogenations, reductive amination and the like. These manipulationsare discussed in standard texts such as March's Advanced OrganicChemistry (3d Edition, 1985, Wiley-Interscience, New York), Feiser andFeiser's Reagents for Organic Synthesis, and in the various volumes andeditions of Methoden der Organischen Chemie (Houben-Weyl), and the like.Many general methods for preparation of starting materials comprisingvariously substituted heterocyclic, hetereoaryl, and aryl rings (theprecursors of Ar, hAr¹, and/or hAr²) can be found in Methoden derOrganischen Chemie (Houben-Weyl), whose various volumes and editions areavailable from Georg Thieme Verlag, Stuttgart. The entire disclosures ofthe treatises recited above are hereby incorporated by reference intheir entireties for their teachings regarding methods for synthesizingorganic compounds and their precursors.

The skilled artisan will also readily appreciate that certain reactionsare best carried out when other functionality is masked or protected inthe molecule, thus avoiding any undesirable side reactions and/orincreasing the yield of the reaction. Often the skilled artisan utilizesprotecting groups to accomplish such increased yields or to avoid theundesired reactions. These reactions are found in the literature and arealso well within the scope of the skilled artisan. Examples of many ofthese manipulations can be found for example in T. Greene and P. Wuts,Protecting Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons(1999).

The following abbreviations used in the examples and elsewhere hereinhave the indicated meanings:

-   -   CH₃CN=Acetonitrile    -   CHCl₃=Chloroform    -   DIC=N,N′-Diisopropylcarbodiimide    -   DIPEA=Diisopropylethylamine    -   DMAP=4-(dimethylamino)-pyridine    -   DMF=N,N-dimethylformamide    -   EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochoride    -   DCM=Dichloromethane        -   ESIMS=electron spray mass spectrometry    -   Et₃N=triethylamine    -   EtOAc=ethyl acetate    -   EtOH=Ethyl Alcohol    -   Fmoc=N-(9-fluorenylmethoxycarbonyl-    -   HCl=Hydrochloric acid    -   H₂SO₄=Sulfuric acid    -   HOBt=1-Hydroxybenzotriazole    -   MeOH=Methyl Alcohol    -   MgSO₄=magnesium sulfate    -   NaHCO₃=sodium bicarbonate    -   NaOH=Sodium Hydroxide    -   Na₂SO₄=Sodium Sulfate    -   Ph=phenyl    -   r.t.=room temperature    -   SPOS=solid phase organic synthesis    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography

Alkyl Group Abbreviations

-   -   Me=methyl    -   Et=ethyl    -   n-Pr=normal propyl    -   i-Pr=isopropyl    -   n-Bu=normal butyl    -   i-Bu=isobutyl    -   t-Bu=tertiary butyl    -   s-Bu=secondary butyl    -   n-Pen=normal pentyl    -   i-Pen=isopentyl    -   n-Hex=normal hexyl    -   i-Hex=isohexyl

Polymer Supported Reagent Abbreviations

-   -   PS-Trisamine=Tris-(2-aminoethyl)amine polystyrene    -   PS-NCO=methylisocyanate polystyrene    -   PS-TsNHNH₂=toluensulfonylhydrazone polystyrene

Example Procedures for Making the Heteroaryl Compounds of Formula (I)

As shown in Scheme 1A, carboxylic acid derivatives of the Ar radical canbe activated by conversion to acid chlorides (METHOD A) or carbodiimideesters (METHOD B), which react with thiosemicarbazide providingintermediate triazole-thiones that can reacts with alkyl substitutedderivatives of hAr² comprising suitable leaving groups (“LG” such aschlorides, bromides, iodides, tosylates, and the like) to providingtriazole derivatives having structures that are within the scope ofFormula (I).

As shown in scheme 1B, 1,2,4-triazole derivatives (I) can bealternatively prepared in two steps from amide precursors of the Ar ringvia treatment with strong bases, carbon disulfide and an electrophilicprecursor of the hAr² radical to form an acylcarbonodithioimidateintermediate, which in presence of hydrazine is converted to the desiredtriazole product. (See M Sato et al., Synthesis, 7, 1981, 554-557).

As shown in scheme 1C, an N-substituted triazole within the scope ofFormula (I) can be obtained in multistep process starting from an amineprecursor of the N-substituent for the triazole, by treatment withcarbon disulfide and methyl iodide to provide a dithiocarbamate, whichcan be reacted with hydrazine to provide a thiosemicarbazide, which canbe condensed with a carboxylic acid precursor of Ar, to give cyclicmercaptotriazole that can be alkylated using appropriate electrophilicprecursors of hAr², such as an alkyl iodide. (See Ashton et al., J. Med.Chem. 1992, 35, 2103-2112).

As shown on scheme 1D, 1,2,4-triazol-5-aminoderivatives can be preparedin two steps from methylester precursors of Ar, by reaction withguanidine under basic conditions providing a 5-amino-triazoleintermediate that reacts with electrophiles such as isothiocyanates toprovide an N-thioacyl triazole compound, which can then be condensedwith an electrophillic precursor of hAr² and hydrolyzed. (See Y. Naitoet al., J. Med. Chem. 39, 15, 1996, 3019-3029).

As shown on scheme 1E, 1,2,4-triazol-5-aminoderivatives (I) can bealternatively prepared by reacting orthoester precursors of Ar withcyanoamine and acetic anhydride to provide an N-cyanomidate which isthen reacted with hydrazine to provide the 3-amino-tetrazole, which canbe reacted with electrophillic precursors of hAr². (See K. R. Husfmannet al., J. Org. Chem. 28, 1963, 1816-1821).

As shown in scheme 2A, 1,3,4-oxadiazoles (I) can be prepared fromhydrazide precursors of Ar and acid chlorides precursors of hAr². (SeeB. G. Szczepankiewicz et al., J. Med Chem. 2001, 44, 4416-4430).

As shown in scheme 2B N-cyanomidates (prepared as shown above in Scheme1E) react with hydroxylamine providing 5-amino-1,2,4-oxadiazoles (II)that can be alkylated or acylated to give N,3-disubstituted1-1,2,4-oxadiazol-5-amines. (See K. R. Husfmann et al., J. Org. Chem.28, 1963, 1816-1821).

As shown in scheme 2C, hydrazide precursors of Ar can be treated withcyanogen bromide in EtOH to provide 1,3,4-oxadizolylamines that can beconverted to substituted triazoles or oxadiazoles within the scope ofthe compounds of Formula (I). See PCT Patent Publication WO 02/078696 toMarino et al., page 14, published Oct. 10, 2002.

As shown in scheme 3A oxadiazole intermediate (See preparation in Scheme2B) can rearrange with sulphur nucleophiles under UV irradiation toprovide 1,2,4-thiadiazol-5-amines. (See N. Vivona et.al., Tetrahedron53,37,1997, 12629-12636).

As shown in scheme 3B 1,3,4-thiadiazoles can be prepared by reacting BOCprotected hydrazides with Lawesson's Reagent in the presence oftrifluoroacetic acid, to form thiohydrazides, which react withsubstituted aldehydes by spontaneous cyclization. (See B. G.Szczepankiewicz et al., J. Med Chem. 2001, 44, 4416-4430).

Many substituted and unsubstituted bromo-nitro pyridines, such ascompound (4A1) in Scheme 4A, are commercially available, or are readilysynthesized by methods well known to those of ordinary skill in the art.Reduction of the nitro groups of compounds (4A1) by various methods,including treatment with SnCl₂, can provide the aminopyridines (4A2).Alternatively, many amino pyridines (4A2) are also commerciallyavailable.

Bromopyridines such as (4A2), or (similar pyridines comprising triflatesubstituents) can be used for palladium catalyzed Suzuki coupling witharylboronic acid precursors of the Ar ring of the compounds of Formula(I), to afford the coupled-aromatic pyridine (4A4). The preparation ofthe required aryl boronic acids and procedures for Suzuki Coupling arewell known in the art, and are disclosed for example by Suzuki, Pure &Applied Chem., 66:213-222 (1994), Miyaura and Suzuki, Chem. Rev.95:2457-2483 (1995), Watanabe, Miyaura and Suzuki, Synlett. 207-210(1992), Littke and Fu, Angew. Chem. Int. Ed., 37:3387-3388 (1998),Indolese, Tetrahedron Letters, 38:3513-3516 (1997), Firooznia, et al.,Tetrahedron Letters 40:213-216 (1999), and Darses, et al., Bull. Soc.Chim. Fr. 133:1095-1102 (1996); all incorporated herein by reference.

The coupled-aromatic pyridine (4A4) can be treated with a base and analkylating agent such as for example VI to provide the electrophillicpyridine derivative precursor of hAr², to yield compounds of Formula(I).

Alternatively, the amino intermediate (4A4) can be prepared by firstSuzuki coupling of the bromo-nitro-pyridine (4A1) with an Aryl boronicacid, and then reduction of the nitro group, to provide the aminecompound (4A3). An analogous series of reactions wherein the NH₂ groupof compound (4A2) is replaced by a hydroxyl or sulfhydril group, or aprotected derivative thereof, then subjected to Suzuki coupling andalkylation, and optional oxidation of the sulfur analogs with organicperacids, provides a ready synthetic route to compounds of Formula (I)wherein X is O, S, SO, or SO₂.

Similarly, synthesis of pyrimidine and pyrazine derivatives startingfrom commercially available bromo amino pyrimidines or pyridines can beaccomplished analogously to the reactions described above, or inaccordance with Scheme 4B as shown below:

Bromo pyrimidine or pyrazine starting materials that are readilyavailable can be alkylated by electrophillic precursors of hAr² and abase to provide synthetic intermediates with linked hAr¹ and hAr²radicals, which in turn can undergo Suzuki coupling with an arylboronicacid precursor of Ar to provide the desired pyrimidine and pyrazinecompounds of Formula (I).

As shown in Scheme 5, 3-(arylthio)-pyridazines (5A5) can be prepared inseveral steps by condensing desirably substituted acetophenoneprecursors of the Ar group (5A1) with α-ketoacids to give an acyclicketo-acid intermediate, which is then condensed with hydrazine to yielda cyclization product (5A2), that is precursor to hAr¹. (5A2) can betreated with POCl₃ to yield the cyclic monochloride intermediate (5A3),which can react with thiourea to providing cyclic thiones of Formula(5A4), which are then alkylating agent precursors of hAr2, such ashalides, tosylates, and the like, giving the desired3-(arylthio)-pyridazines (5A5). See J. Med. Chem. 2001, 44, 2707-2718(J.-M. Contreras); and Molecules, 2003, 8, 322-332 (G. H. Sayed).

Scheme 6—Method of Preparing 3-(aryloxy) or 3 (arylamino)-OptionallySubstituted

As shown in scheme 6A, chloropyridazine (5A3) (see scheme 5) can beconverted to the optionally substituted (6A2a) or (6A2b) by reactingwith the corresponding primary alcohol (6A1a) or amine (6A1b), see J.Med. Chem. 2001, 44, 2707-2718 (J. -M. Contreras);

As shown in scheme 6B, unsubstituted pyridazines (6A6a) and (6A6b) canbe prepared starting from the symmetrical dichloropyridazine (6A3) bytreatment with the corresponding alcohol (6A1a) or amine (6Alb) followedby Suzuki coupling in presence of the boronic acid (6A5). Alternativelyunsubstituted pyridazines (6A6a) and (6A6b) can be first coupled to theboronic acid (6A5) to provide the chloropyridazines (6A7a) and (6A7b)that can be treated with the alcohol (6A1a) or amine (6A1b) to providethe corresponding pyridazines (6A6a) and (6A6b).

As shown in scheme 7, 1,4-disubstituted-1,2,3-triazoles (7A3) can beprepared using a microwave assisted three-component reaction from alkylhalide (7A1), sodium azide and alkyne (7A2), see P. Appukkuttan et alOrg. Lett. 2004, 6, 23, 4223-4225.

As shown in scheme 8, 2,5-disubstituted-2H-tetrazole (8A3) can beprepared from the nitrile (8A1) by reacting with trimethylsilyl azide(TMSiN₃) and tetrabutylammonium bromide (TBAF) See D. Amantini J. Org.Chem. 2004, 69,8, 2896-2898), providing the tetrazole intermediate (8A2)that can be alkylated with the alkyl halides (8A4), see J. R. Maxwell,J. Med. Chem. 1984, 27, 1565-1570.

The foregoing example schemes and cited prior art are provided for theguidance of the reader, and represent exemplary methods for making thecompounds of Formula (I) disclosed herein. The prior art articles andpatents cited in the example schemes are hereby incorporated byreference for the purpose of describing the relevant syntheticstrategies and experimental methods. The methods cited above are notlimiting, and it will be apparent to one of ordinary skill in the artthat other synthetic strategies and/or modifications of the schemesdisclosed above can be employed to prepare compounds of Formula (I).Such methods specifically include solid phase based chemistries,including combinatorial chemistry. The skilled artisan is thereforethoroughly equipped to prepare the necessary and/or claimed compounds bythe methods given the cited treatises and literature, and thisdisclosure. The skilled artisan given the literature and this disclosureis well equipped to prepare any of the necessary starting materialsand/or claimed compounds. Nevertheless, in some of the Examples citedbelow, starting materials were not readily available, and therefore weresynthesized, and the synthesis of the starting materials is thereforeexemplified.

Measuring the Biological Activity of the Compounds of the Invention

Cell based technologies and assays, such as those disclosed in WO02/064631, and WO 03/001876, and U.S. Patent Publication US 2003-0232407A1 were used both to initially screen a wide variety of classes ofcompounds for agonist or antagonist activity for T1R1/T1R3 “savory”taste receptors, that had been expressed in appropriate cell lines. Onceinitial “hits” were obtained for compounds screened with such celllines, the same assays and also certain cell and/or receptor-basedassays were used as analytical tools to measure the quantitative abilityof the compounds of Formula (I) to enhance the savory taste of MSG, andwere used to provide empirical data to guide an iterative process ofsynthesizing and testing structural variants of the initial compounds,in combination with occasional human taste testing of high interestspecies compounds, so as to design, test, and identify genuses ofcompounds and species therein having increased and optimized levels ofthe desired biological activities.

Many embodiments of the inventions relate to the identification ofspecific compounds and classes of the amide compounds of Formula (I)that modulate (increase or decrease) the activity of the T1R1/T1R3(preferably hT1R1/hT1R3) savory taste receptor (umami receptor), aloneor in combination with another compound that activates hT1R1/hT1R3,especially MSG. Particularly, many embodiments the invention relate tothe linked heteroaryl compounds of Formula (I) that modulate theactivity of hT1R1/hT1R3 (human umami receptor) in vitro and/or in vivo.In another aspect, the invention relates to compounds of Formula (I)that modulate the human perception of savory (umami) taste, alone or incombination with another compound or flavorant, such as MSG, when (1)one or more of the compounds of Formula (I) and (2) MSG are added to acomestible composition, with the result that the savory flavor of theMSG is enhanced or multiplied, so that it is necessary to add less MSGto the modified comestible compositions in order to produce the desiredlevel of Umami/savory flavor.

In Vitro hT1R1/hT1R3 Umami Taste Receptor Activation Assay

In order to identify new savory flavoring agents and enhancers,including compounds with savory agonist and enhancer activities (dualactivity), the compounds of Formula (I) were screened in primary assaysand secondary assays including compound dose response and enhancementassay. In a primary assay for potential ability to modulate umami taste,compounds of Formula (I) that can be either savory flavoring agents intheir own right or flavor enhancers of MSG are identified and scores oftheir activities are given as percentage of the maximum MSG intensity(%). In compound dose response, an EC₅₀ is calculated to reflect thepotency of the compound as a savory agonist or enhancer.

An HEK293 cell line derivative (See e.g., Chandrashekar, et al., Cell(2000) 100: 703-711) which stably expresses Gα15 and hT1R1/hT1R3 underan inducible promoter (See WO 03/001876 A2) was used to identifycompounds with savory tasting properties.

Compounds covered in this document were initially selected based ontheir activity on the hT1R1/hT1R3-HEK293-Gα15 cell line. Activity wasdetermined using an automated fluorometric imaging assay on a FLIPRinstrument (Fluorometric Intensity Plate Reader, Molecular Devices,Sunnyvale, Calif.) (designated FLIPR assay). Cells from one clone(designated clone I-17) were seeded into 384-well plates (atapproximately 48,000 cells per well) in a medium containing Dulbecco'smodified Eagle's medium (DMEM) supplemented with GlutaMAX (Invitrogen,Carlsbad, Calif.), 10% dialyzed fetal bovine serum (Invitrogen,Carlsbad, Calif.), 100 Units/ml Penicillin G, 100 μg/ml Streptomycin(Invitrogen, Carlsbad, Calif.), and 60 pM mifepristone (to induceexpression of hT1R1/hT1R3, (See WO 03/001876 A2). 1-17 cells were grownfor 48 hours at 37° C. I-17 cells were then loaded with the calcium dyeFluo-3AM (Molecular Probes, Eugene, Oreg.), 4 μM in a phosphate bufferedsaline (D-PBS) (Invitrogen, Carlsbad, Calif.), for 1.5 hours at roomtemperature. After replacement with 25 μl D-PBS, stimulation wasperformed in the FLIPR instrument and at room temperature by theaddition of 25 μl D-PBS supplemented with different stimuli atconcentrations corresponding to twice the desired final level. Receptoractivity was quantified by determining the maximal fluorescenceincreases (using a 480 nm excitation and 535 nm emission) afternormalization to basal fluorescence intensity measured beforestimulation.

For dose-responses analysis, stimuli were presented in duplicates at 10different concentrations ranging from 1.5 nM to 30 μM. Activities werenormalized to the response obtained with 60 mM monosodium glutamate, aconcentration that elicits maximum receptor response. EC₅₀s(concentration of compound that causes 50% activation of receptor) weredetermined using a non-linear regression algorithm, where the Hillslope, bottom asymptotes and top asymptotes were allow to vary.Identical results were obtained when analyzing the dose-response datausing commercially available software for non-linear regression analysissuch as GraphPad PRISM (San Diego, Calif.).

In order to determine the dependency of hT1R1/hT1R3 for the cellresponse to different stimuli, selected compounds were subjected to asimilar analysis on I-17 cells that had not been induced for receptorexpression with mifepristone (designated as un-induced I-17 cells). Theun-induced I-17 cells do not show any functional response in the FLIPRassay to monosodium glutamate or other savory-tasting substances.Compounds were presented to un-induced umami cells at 10 μM—or threetimes the maximum stimulation used in the dose-response analysis.Compounds covered in this document do not show any functional responsewhen using un-induced umami cells in the FLIPR assay.

In some aspects of the present invention, an EC₅₀ of lower than about 10mM is indicative of compounds that induce T1R1/T1R3 activity and isconsidered a savory agonist. Preferably a savory agonist will have EC₅₀values of less than about 1 mM; and more preferably will have EC₅₀values of less than about 20 μM, 15 μM, 10 μM, 5 μM, 3 μM, 2 μM, 1 μM,0.8 μM or 0.5 μM.

In umami taste enhancement activity assay experiments, also produce an“EC₅₀ ratio” measurement of how effectively the amide compounds of theinvention enhance the savory flavorant (typically MSG) already in a testsolution. A series of measurements of the dose response is run insolutions comprising MSG alone, then a second dose response is run withMSG in combination with predetermined amounts of a candidate compound ofFormula (I) at the same time.

In this assay, increasing concentrations of monosodium glutamate(ranging from 12 μM to 81 mM) were presented, in duplicates, in thepresence or absence of a fixed concentration of the test compound.Typical compound concentrations tested were 30 μM, 10 μM, 3 μM, 1 μM,0.3 μM, 0.1 μM and 0.03 μM. The relative efficacy of compounds ofFormula (I) at enhancing the receptor was determined by calculating themagnitude of a shift in the EC₅₀ for monosodium glutamate. Enhancementwas defined as a ratio (EC₅₀R) corresponding to the EC₅₀ of monosodiumglutamate, determined in the absence of the test compound, divided bythe EC₅₀ of monosodium glutamate, determined in the presence of the testcompound. Compounds exhibiting EC₅₀R>2.0 were considered enhancers.

Stated alternatively, “EC₅₀ ratio” as compared to MSG is calculatedbased on the following definitions:EC₅₀Ratio vs. MSG=EC₅₀(MSG)/EC₅₀(MSG+[Compound])

-   -   wherein “[compound]” refers to the concentration of the compound        of Formula (I) used to elicit (or enhance or potentiate) the MSG        dose response.

It should be noted that the EC₅₀ ratio measured can depend somewhat onthe concentration of the compound itself. Preferred savory enhancerswould have a high EC₅₀ Ratio vs. MSG at a low concentration of thecompound used. Preferably the EC₅₀ ratio experiments to measure umamienhancement are run at a concentration of a compound of Formula (I)between about 10 μM to about 0.1 ∥M, or preferably at 1.0 μM or 3.0 μM.

An EC₅₀ ratio of greater than 1 is indicative of a compound thatmodulates (potentiates) hT1R1/hT1R3 activity and is a savory enhancer.More preferably, the savory taste enhancer compounds of Formula (I) willhave EC₅₀ ratio values of at least 1.2, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0, or10.0, or even higher.

In one aspect, the extent of savory modulation of a particular compoundis assessed based on its effect on MSG activation of T1R1/T1R3 in vitro.It is anticipated that similar assays can be designed using othercompounds known to activate the T1R1/T1R3 receptor.

Specific compounds and generic classes of compounds that been shown tomodulate hT1R1/hT1R3 based on their EC₅₀ ratios evaluated according tothe above formula are identified in the detailed description of theinvention, the examples, and the claims.

The procedures used for human taste testing of the umami/savorycompounds of Formula (I) are reported hereinbelow. Comparable EC₅₀assays for activity of the compounds of Formula (I) for sweet receptoragonism and/or sweet taste perception in humans are also reportedhereinbelow.

EXAMPLES

The following examples are given to illustrate a variety of exemplaryembodiments of the invention and are not intended to be limiting in anymanner.

For the purpose of this document, the compounds individually disclosedin the following Examples 1-12 and corresponding Tables A and B can bereferred in shorthand by the number of the example. For example, asshown immediately bellow, Example 1 discloses a synthesis of aparticular compound2-((5-(2-methoxy-4-methylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine,and the results of experimental assays of its biological effectiveness,which compound is and can be referred to herein in shorthand form asCompound 1. Similarly, the first compound illustrated in Table A can bereferred to elsewhere herein as Compound A1.

Example 12-((5-(2-methoxy-4-methylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

To a solution of5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (Example 1a)(110 mg, 0.5 mmol) in 2 ml of EtOH was added 2-(bromomethyl)pyridinehydrobromide (152 mg, 0.6 mmol). The suspension was heated at 60° C. for22 h. The reaction was diluted with EtOAc and washed with water, brine,dried over MgSO₄ filtered and evaporated to produce an oil. The oil waspurified on a preparative TLC plate to produce the desired product(72%). ¹H NMR (500 MHz, CDCl₃): δ 2.40 (s, 3H), 3.99 (s, 3H), 4.55 (s,2H), 6.84 (s, 1H), 6.92-6.93 (d, 1H), 7.16-7.19 (dd, 1H), 7.53-7.55 (d,1H), 7.62-7.65 (m, 1H), 8.15-8.17 (d, 1H), 8.56-8.57 (d, 1H). MS (M+H,313).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.08 μM, and when present at 0.03 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of5.9.

Example 1a 5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione

To a solution of 2-methoxy-4-methylbenzoic acid (1.81 g, 9.22 mmol) in 9ml of pyridine was added EDCI (1.9 g, 9.3 mmol) and the suspension wasstirred at r.t. for 1 h. Then thiosemicarbazide (800 mg, 8.8 mmol) wasadded and the reaction was stirred at r.t. for 21 h. The mixture wasevaporated to dryness and then diluted with water. The white solid wasthen filtered, washed with water and suspended in 20 ml 1 M aq. NaHCO₃and then heated at reflux for 2 days. The suspension was filtered hotand the aqueous solution was cooled in ice and acidified to pH 3 withconc. HCl. The solid was filtered and washed with water and dried togive a white powder (47%).

Example 22-((5-(2-methoxy-4-methylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)-5-methylpyridine

Prepared in a similar manner to example 1 using5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 1a)and 2-(chloromethyl)-5-methylpyridine (example 2a). Yield 14%. ¹H NMR(500 MHz, CDCl₃): δ2.29 (s, 3H), 2.41 (s, 3H), 4.00 (s, 3H), 4.51 (s,2H), 6.75 (s, 1H), 6.90 (s, 1H), 7.40 (s, 1H), 8.1 (d, 1H), 8.4 (s, 1H),11.5-11.7 (bs, 1H). MS(M+H, 327.1).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.49 μM.

Example 2a 2-(chloromethyl)-5-methylpyridine

2,5-Dimethylpyridine (5.18 ml, 44.8 mmol) was mixed with DCM (100 mL)and cooled in an ice bath. MCPBA (15.5 g, 2 eq.) was then added inportions over 30 min. The solution was stirred at r.t. overnight. Thereaction mixture was then washed with aq. NaHCO₃, brine, dried andevaporated to produce an N-oxide that was used without furtherpurification. A solution of the N-oxide (2.22 g, 18 mmol), p-TsCl (5.15g, 27 mmol) in DCM (3 mL) was heated at 40° C. under argon for 2 h. Thesolution was then added dropwise to a solution of triethylamine (3.8 mL,27 mL) in DCM (18 mL) while heating at 40° C. under argon. The orangesolution was heated at 40° C. for an additional 3 h. Then the mixturewas cooled, neutralized with solid NaHCO₃ (2 g) and evaporated undervacuum. The crude material was dissolved in MeOH (24 mL) to give anestimated product in 0.75 M solution. The crude solution of2-(chloromethyl)-5-methylpyridine was used in the next step withoutfurther purification.

Example 32-((5-(2,4-dimethylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using 5-(2,4dimethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 3a) and2-(bromomethyl)pyridine hydrobromide. Yield 64%. ¹H NMR (500 MHz,CDCl₃): δ 2.34 (s, 3H), 2.57 (s, 3H), 4.37 (s, 2H), 4.51 (s, 2H),7.04-7.08 (m, 2H), 7.28-7.31 (m, 1H), 7.41-7.43 (d, 1H), 7.74-7.77 (m,2H), 8.63-8.64 (d, 1H). MS(M+H, 297); mp=112-114° C.

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.09 μM, and when present at 0.01 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of4.3.

Example 3a 5-(2,4 dimethylphenyl)-2H-1,2,4-triazole-3(4H)-thione

A suspension of thiosemicarbazide (800 mg, 8.78 mmol) in 9 mL ofpyridine was added 2,4-dimethylbenzoyl chloride (1.68 g, 10 mmol). Thereaction was heated at 150° C. for 10 min using a microwave synthesizer.The yellow solution was evaporated to dryness and then diluted withwater. The white solid was then collected and washed with water. Thesolid was suspended in 20 mL of 1 M aq. NaHCO₃. The suspension washeated at 180° C. for 1 h using a microwave synthesizer. Then themixture was filtered hot and the aqueous solution was cooled in ice andacidified to pH 3 with conc. HCl. The solid was filtered and washed withwater and dried to give white powder (43%).

Example 42-((5-(4-Ethylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using5-(4-ethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 4a) and2-(bromomethyl)pyridine hydrobromide. Yield 71%. ¹H NMR (500 MHz, dMSO):δ 1.18-1.22 (t, 3H), 2.64-2.66 (t, 2H), 4.52 (s, 2H), 7.30-7.88 (m, 8H),14.3 (bs, 1H). MS(M+H, 297).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.14 μM, and when present at 0.03 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of4.4.

Example 4a 5-(4-Ethylphenyl)-2H-1,2,4-triazole-3(4H)-thione

Prepared in a similar manner to example 3a using 4-ethylbenzoyl chloride(yield 65%).

Example 52-((5-(4,5-dimethylfuran-2-yl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a)and 2-(bromomethyl)pyridine hydrobromide. Yield 27%. ¹H NMR (500 MHz,dMSO): δ 1.98 (s, 3H), 2.28 (s, 3H), 4.37 (s, 2H), 6.76 (s, 1H), 7.3(m,1H), 7.45 (d, 1H), 7.75 (t, 1H), 8.6 (s, 1H). MS(M+H, 287).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.58 μM, and when present at 0.1 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of4.4.

Example 5a 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione

Prepared in a similar manner to example 1a using4,5-dimethylfuran-2-carboxylic acid (yield 25%).

Example 62-((5-(4,5-dimethylfuran-2-yl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using5-(benzofuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 6a) and2-(bromomethyl)pyridine hydrobromide. Yield 59%. ¹H NMR (500 MHz,CDCl₃): δ 4.37 (s, 2H), 7.26-7.34 (m, 5H), 7.4-7.42 (d,1H), 7.55-7.57(d, 1H), 7.65-7.67 (d, 1H), 7.75 (t, 1H), 8.62 (s, 1H). MS(M+H, 309).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 2.58 μM, and when present at 0.1 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of2.88.

Example 6a 5-(benzofuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione

Prepared in a similar manner to example 3a using benzofuran-2-carbonylchloride (yield 73%).

Example 72-((5-(2,5-dimethylfuran-3-yl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using5-(2,5-dimethylfuran-3-yl)-2H-1,2,4-triazole-3(4H)-thione (example 7a)and 2-(bromomethyl)pyridine hydrobromide. Yield 70%. ¹H NMR (500 MHz,CDCl₃): δ 2.27 (s, 3H), 2.59 (s, 3H), 4.32 (s,2H), 6.35 (s, 1H),7.28-7.29 (d, 1H), 7.35-7.36 (d, 1H), 7.75 (t, 1H) 8.62 (s, 1H). MS(M+H,287).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 2.07 μM, and when present at 0.1 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of2.1.

Example 7a 5-(2,5-dimethylfuran-3-yl)-2H-1,2,4-triazole-3(4H)-thione

Prepared in a similar manner to example 3a using2,5-dimethylfuran-3-carbonyl chloride (yield 72%).

Example 82-(2-(5-(4,5-dimethylfuran-2-yl)-1H-1,2,4-triazol-3-ylthio)ethyl)pyridine

Prepared in a similar manner to example 1 using5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a)and 2-(2-bromoethyl)pyridinium bromide (example 8a). Yield 55%. ¹H NMR(500 MHz, CDCl₃): δ 1.96 (s, 3H), 2.24 (s, 3H), 3.28 (t,2H), 3.49 (t,2H), 6.77 (s, 1H), 7.13-7.23 (m, 2H), 7.65 (t, 1H) 8.58 (s, 1H). MS(M+H,301).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 1.87 μM, and when present at 0.1 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of2.66.

Example 8a 2-(2-bromoethyl)pyridinium bromide

To a solution of 2-(2-hydroxyethyl)pyridine (3 ml, 26.6 mmol) was added30 ml of 33% HBr in acetic acid. The yellow solution was heated in thecapped vial at 78° C. for 2 days. The reaction was evaporated under highvacuum to produce a brown solid. The solid was re-crystallized from hotisopropanol to produce a light tan solid (73%). ¹H NMR (500 MHz, dMSO):δ 3.62-3.65 (t, 2H), 3.95-3.98 (t, 2H), 7.95 (t,1H), 8.09-8.10 (d, 1H),8.58 (t, 1H), 8.90 (d, 1H).

Example 92-((5-(2,4-dimethoxybenzyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using5-(2,4-dimethoxybenzyl)-2H-1,2,4-triazole-3(4H)-thione (example 9a) and2-(bromomethyl)pyridine hydrobromide. Yield 34%. ¹H NMR (500 MHz,CDCl₃): δ 3.77 (s, 3H), 3.79 (s, 3H), 4.0 (s, 2H), 4.34 (s,2H),6.35-6.45 (m, 2H), 7.1 (d, 1H), 7.15 (t, 1H), 7.3 (d, 1H), 7.7 (t, 1H),8.5 (s, 1H). MS(M+H, 343).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 1.2 μM, and when present at 0.1 μMenhanced the effectiveness of monosodium glutamate with an EC₅₀ ratio of2.66.

Example 9a 5-(2,4-dimethoxybenzyl)-2H-1,2,4-triazole-3(4H)-thione

Prepared in a similar manner to example la using 2,4-dimethoxyphenylacetic acid. ¹H NMR (500 MHz, CDCl₃): δ 3.80 (s, 3H), 3.90 (s, 3H),6.4-6.5 (m, 2H), 7.1 (bs,1H), 9.8 (bs, 1H), 10.2 (bs, 1H).

Example 102-((5-(4-Ethyl-2-methylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

Prepared in a similar manner to example 1 using5-(4-ethyl-2-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 10a)and 2-(bromomethyl)pyridine hydrobromide. Yield 39%. ¹H NMR (300 MHz,dMSO): δ 1.17-1.22 (t, 3H), 2.46 (s, 3H), 2.60-2.64 (dd, 2H), 4.50 (s,2H), 7.14-7.18 (m, 2H), 7.27-7.29 (m, 1H), 7.47-7.49 (d, 1H), 7.58 (bd,1H), 7.72-7.77 (m, 1H), 8.50-8,51 (d, 1H). MS(M+H, 311).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.02 μM.

Example 10a 5-(4-Ethyl-2-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione

Prepared in a similar manner to example 1 a using4-ethyl-2-methylbenzoic acid (example 10b). Yield 59%. MS (M+H, 220).

Example 10b 4-Ethyl-2-methylbenzoic acid

Methyl 4-ethyl-2-methylbenzoate (example 10c) (2.37 g) was dissolved inaq. NaOH (1M, 40 mL) and the solution heated at 60° C. overnight. Themixture was washed with hexanes and the aqueous layer was acidified with6N HCl to pH 2. The title product was obtained as a white precipitate,following filtration and drying (2.17 g, 80%).

Example 10c Methyl 4-ethyl-2-methylbenzoate

4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml ofMeOH with 1 ml of concentrated H₂SO₄. The mixture was refluxedovernight, MeOH was evaporated and the residue was extracted with EtOAc,dried over MgSO₄ filtered and evaporated to give methyl4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%)that was used in the next step without further purification. The ester(2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL)and NMP (9 mL) and Iron (III) acetylacetonate (318 mg, 0.9 mmol) wasadded giving a red solution. Then EtMgBr (7 ml of 1M solution in ether)was added dropwise under vigorous stirring. The mixture turned darkbrown and then violet and then was stirred for 15 more min. The reactionwas diluted with ether and quenched upon the addition of aq. HCl (1M, 10ml). The crude product was extracted with ether. The combined organiclayers were washed with water and brine, dried over MgSO₄ andevaporated. The residue was purified on silica gel (30% EtOAc/hexanes)to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (¹H NMR(500 MHz, CDCl₃): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b,2H), 7.85 (d, 1H)).

Example 11 2-((4-p-Tolyl-1H-1,2,3-triazol-1-yl)methyl)pyridine

A mixture of tBuOH (1.5 mL), water (1.5 mL), 2-(bromomethyl)pyridine(253 mg, 1 mmol), 1-ethynyl-4-methylbenzene (122 mg, 1.05 mmol) and NaN₃(68 mg, 1.05 mmol) was added to a microwaveable vial. A cooper wire (50mg) and CuSO₄ (200 μl of 1M aq. solution) was added to the stirredsuspension. The vial was sealed and the mixture was irradiated(Microwave, Personal Chemistry, Biotage from Upsala Sweden) at 125° C.for 5 min. The mixture was then diluted with water and the product wasextracted to EtOAc, washed with 1M ammonium citrate, 0.25 M aq. HCl andbrine, dried over MgSO₄, filtered and evaporated. The crude product waspurified on silica gel (Eluent: 10% MeOH in DCM) to give2-((4-p-Tolyl-1H-1,2,3-triazol-1-yl)methyl)pyridine (88 mg, 35%). ¹H NMR(300 MHz, dMSO): δ 2.30 (s, 3H), 5.72 (s, 2H), 7.30-7.45 (m, 4H),7.77-7.89 (m, 3H), 8.60 (s, 1H); MS (M+H, 251).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 4.66 μM.

Example 12 2-(2-(4-p-Tolyl-1H-1,2,3-triazol-1-yl)ethyl)pyridine

Prepared in a similar manner to example 11 using2-(2-bromoethyl)pyridine hydrobromide. Yield 74 mg, 28%. ¹H NMR (300MHz, dMSO): δ 2.30 (s, 3H), 3.99 (s, 3H), 3.36-3.38 (m, 2H), 4.76-4.79(m, 2H), 7.21-7.23 (m, 4H), 7.65-7.67 (m, 3H), 7.53-7.55 (d, 1H), 8.46(s, 1H); MS (M+H, 265).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 16.35 μM.

Example 13 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethylthio)pyridazine

To a mixture of 2-(bromomethyl)pyridine hydrobromide (116 mg; 0.46 mmol)and 6-(2,4-dimethylphenyl)pyridazine-3(2H)-thione (Example 13a) (100 mg,0.46 mmol) in EtOH (3 mL) was added EtONa (20% in EtOH, 25 μl) and thereaction was irradiated in a microwave at 140° C. for 4 min. The crudemixture was dried down and purified on silica gel (Eluent: 5% MeOH inDCM) to give 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethylthio)pyridazine(49 mg, 35%) as a white solid. ¹H NMR (300 MHz, dMSO: δ 2.49 (s, 3H),2.54 (s, 3H), 4.09 (s, 2H), 6.32-6.37 (m, 2H), 6.45-6.52 (m, 2H),6.75-6.78 (d, 1H), 6.84-6.87 (m, 2H), 6.95-6.98 (t, 1H), 7.67-7.68(d,1H); MS (M+H, 308).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 1.5 μM.

Example 13a 6-(2,4-Dimethylphenyl)pyridazine-3(2H)-thione

3-chloro-6-(2,4-dimethylphenyl)pyridazine (example 13b) (1.36 g) wasrefluxed with thiourea (473 mg, 6.2 mmol) in EtOH (25 mL) for 5 hrs. Themixture was evaporated, and water (45 mL) was added to the residue,followed by Na₂CO₃ (318 mg, 3 mmol). The precipitate that formed wascollected by filtration, washed with diethylether and dried to give6-(2,4-Dimethylphenyl)pyridazine-3(2H)-thione (1.12 g, 52%). ¹H NMR (300MHz, dMSO): δ 2.29 (s, 3H), 2.32 (s, 3H), 7.12-7.30 (m, 2H), 7.29-7.31(d, 1H), 7.46-7.49 (d, 1H), 7.65-7.68 (dd, 1H); MS (M+H, 217).

Example 13b 3-chloro-6-(2,4-dimethylphenyl)pyridazine

6-(2,4-dimethylphenyl)pyridazin-3(2H)-one (example 13c) was heated withPOCl₃ (5.15 ml, 55 mmol) at 85° C. for 4 hours. Following cooling andtreating with crushed ice a white solid obtained and was collected togive 1.36 g of the 3-chloro-6-(2,4-dimethylphenyl)pyridazine. ¹H NMR(300 MHz, dMSO): δ 2.29 (s, 3H), 2.34 (s, 3H), 7.16-7.19 (m, 2H),7.35-7.37 (d, 1H), 7.93-8.00 (dd, 2H); (M+H, 313).

Example 13c 6-(2,4-dimethylphenyl)pyridazin-3(2H)-one

A mixture of glyoxylic acid monohydrate (920 mg, 10 mmol) and2′,4′-dimethylacetophenone (4.45 mL, 30 mmol) was stirred at 150° C. for2 hr. Then the mixture was cooled down to room temperature and water (4mL) was added followed by conc. aq. NH₄OH (1 mL). The mixture was washedwith DCM. To the ammoniac solution was added hydrazine (314 μL, 10 mmol)and the solution was refluxed for 3 hours. After cooling to roomtemperature the precipitate was collected by filtration to give thedesired product as a white powder (1.1 g, 55%), ¹H NMR (300 MHz, dMSO):δ 2.22 (s, 3H), 2.25 (s, 3H), 6.93-6.95 (d, 1H), 7.15 (m, 3H), 7.21-7.23(d, 1H), 7.57-7.61 (d, 1H), 13.1 (bs, 1H); (M+H, 201).

Example 14 3-(Benzylthio)-6-(2,4-dimethylphenyl)pyridazine

Prepared in a similar manner to example 13 using benzyl bromide and6-(2,4-dimethylphenyl)pyridazine-3(2H)-thione (Example 13a). Yield 53.5mg (38%). ¹H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.34 (s, 3H), 4.60 (s,2H), 7.16-7.17 (m, 2H), 7.30-7.34 (m, 4H), 7.47-7.49 (d, 2H), 7.64-7.72(m, 2H); MS (M+H, 307).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 2.7 μM.

Example 15 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethoxy)pyridazine

3-Chloro-6-(pyridin-2-ylmethoxy)pyridazine (Example 15a) (221 mg, 1mmol) was dissolved in toluene (10 mL), EtOH (2 mL), and water (1.5 mL).Then 2,4-dimethylphenylboronic acid (150 mg, 1 mmol) was added, followedby K₂CO₃ (276 mg, 2 mmol) and the mixture was degassed using argonstream.

Tetrakis(triphenylphosphine)palladium (232 mg, 0.2 mmol) was added underargon and the mixture was refluxed overnight. The solvents were removedunder vacuum and a residual solid was extracted with EtOAc, andsuccessively washed with water and brine dried over MgSO₄ filtered andevaporated. The crude material was purified on silica gel (Eluent: 50%EtOAc in hexanes) to give3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethoxy)pyridazine (169 mg, 58%)as a white solid. ¹H NMR (300 MHz, dMSO): δ 2.26 (s, 3H), 2.32 (s, 3H),5.62 (s, 2H), 7.13-7.15 (m, 2H), 7.28-7.40 (m, 2H), 7.55-7.56 (d, 1H),7.78-7.84 (m, 2H), 8.58-8.60 (d, 1H); MS (M+H, 292).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 6.9 μM.

Example 15a 3-Chloro-6-(pyridin-2-ylmethoxy)pyridazine

To a solution of NaH (1.44 g, 36 mmol, 60% in mineral oil) in THF (15mL) was added pyridin-2-ylmethanol (1.16 ml, 12 mmol) and the mixturewas stirred for 30 min at rt. Then 3,6-dichloropyridazine (1.79 g, 14mmol) was added and the mixture was stirred at 55° C. for 4 hours. Thereaction was quenched with water and sat. NaHCO₃ was added. The productwas then extracted with EtOAc, dried over MgSO₄ filtered and evaporated.The residue was purified on silica gel(Eluent: 80% EtOAc in hexanes) togive 3-chloro-6-(pyridin-2-ylmethoxy)pyridazine as a white solid (1.64g, 62%). ¹H NMR (300 MHz, dMSO): δ 5.57 (s, 2H), 7.35-7.38 (m, 1H),7.48-7.54 (m, 2H), 7.82-7.88 (m, 2H), 8.57-8.59 (dd, 1H); MS (M+H, 222).

Example 165-(2,4-Dimethylphenyl)-N-(pyridin-2-ylmethyl)-1,3,4-oxadiazol-2-amine

To a solution of 5-(2,4-dimethylphenyl)-1,3,4-oxadiazol-2-amine (Example16a) (94.5 mg, 0.5 mmol) in 5 ml of dry acetonitrile was added K₂CO₃(207 mg, 1.5 mmol). To the suspension was added 2-(bromomethyl)pyridinehydrobromide (127 mg, 0.5 mmol) and the mixture was stirred at 90° C.overnight. The solvent was removed under vacuum and the solid wasdissolved in EtOAc, washed successively with aq. NaHCO₃ and brine, driedover MgSO₄ filtered and evaporated. The residue was purified on silicagel to give5-(2,4-Dimethylphenyl)-N-(pyridin-2-ylmethyl)-1,3,4-oxadiazol-2-amine(136 mg, 97%) as a white solid. ¹H NMR (300 MHz, CdCl₃): δ 2.34 (s, 3H),2.5 (s, 3H), 5.1 (s, 2H), 7.07-7.08 (m, 2H), 7.21-7.33 (m, 2H),7.64-7.68 (m, 2H), 8.59-8.60 (d, 1H); MS (M+H, 281).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 10.3 μM.

Example 16a 5-(2,4-Dimethylphenyl)-1,3,4-oxadiazol-2-amine

To a solution of 2,4-dimethylbenzohydrazide (example 16b) (2 g) in drydioxane (12 mL) was added cyanic bromide (1.28 g, 12.2 mmol) followed bya solution of NaHCO₃ (1.02 g, 12.2 mmol) in water (12 mL). The resultingmixture was stirred 2 hours at rt. The solution was concentrated to ½volume on vacuum and diluted with water (20 mL). The resulting solid wascollected and dried on vacuum to give5-(2,4-Dimethylphenyl)-1,3,4-oxadiazol-2-amine (1.88 g, 82%) as a whitesolid. ¹H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.52 (d, 3H), 7.13 (d,1H), 7.16 (s, 3H), 7.54-7.56 (d, 1H); MS (M+H, 190).

Example 16b 2,4-dimethylbenzohydrazide

To a solution of methyl 2,4-dimethylbenzoate (2 g, 12.2 mmol) in MeOH(10 mL) was added anhydrous hydrazine (1.95 mL, 61 mmol) and the mixturewas heated under reflux for 40 hours. Then the mixture was evaporatedand dried under vacuum to give 2,4-dimethylbenzohydrazide as a whitesolid (2 g, 100%; MS (M+H, 165).

Example 17 3-(Benzylthio)-6-(2,4-dimethylphenyl)pyridazine

Prepared in a similar manner to example 13 using 3-(bromomethyl)pyridinehydrobromide 6-(2,4-dimethylphenyl)pyridazine-3(2H)-thione (Example13a). Yield 39.5 mg (28%). ¹H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.34(s, 3H), 4.62 (s, 2H), 7.13-7.17 (m, 2H), 7.31-7.37 (m, 2H), 7.65-7.71(m, 2H), 7.89-7.90 (d, 1H), 8.45-8.46(m, 1H), 8.69-8.70 (d, 1H); MS(M+H, 308).

The compound had EC₅₀ for activation of umami receptor expressed in anHEK293 cell line of 15.17 μM.

Example 182-((5-(4-ethyl-2-methoxyphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine

To a solution of5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 18a)(100 mg, 0.43 mmol) in EtOH (2 mL) was added 2-(bromomethyl)pyridinehydrobromide (129 mg, 0.51 mmol). The suspension was heated at 60° C.for 22 h. The reaction mixture was diluted with EtOAc and washedsuccessively with water and brine, dried over MgSO₄, filtered andevaporated. The residue was purified on silica gel (Eluent: 5% MeOH inDCM) to give2-((5-(4-ethyl-2-methoxyphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine(95 mg) as a white powder (68%). ¹H NMR (300 MHz, dMSO): δ 1.19-1.22 (t,3H), 2.63-2.69 (dd, 2H), 3.93 (s, 3H), 4.48 (s, 2H), 6.93-7.03 (m, 2H),7.25-7.29 (m, 1H), 7.49-7.5 (m, 1H), 7.71-7.75 (m, 1H), 7.93-7.95 (d,1H), 8.50-8,51 (d, 1H), 13.65 (bs, 1H), MS (M+H, 327).

The compound had EC₅₀ for activation of a hT1R1/hT1R3 umami receptorexpressed in an HEK293 cell line of 0.05 μM.

Example 18a 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione

To a solution of 4-ethyl-2-methoxybenzoic acid (example 18b) (1 g, 6.1mmol) in pyridine (6 mL) was added EDCI (1.2 g, 6.3 mmol) and thesuspension was stirred at r.t. for 2 h. Then thiosemicarbazide (547 mg,6 mmol) was added and the reaction was stirred at r.t. for 24 h. Themixture was evaporated to dryness and then diluted with water. A whitesolid was collected and washed with water. The solid was suspended inaq. NaHCO₃ (1M, 20 mL) and heated at reflux for 2 days. The suspensionwas filtered hot and the aqueous solution was cooled in ice andacidified to pH 3 with conc. HCl. The solid was collected washed withwater and dried to give5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione as a whitepowder (55%). MS (M+H, 236).

Example 18b 4-Ethyl-2-methoxybenzoic acid

Methyl 4-ethyl-2-methoxybenzoate (example 18c) (2.01 g, 10.3 mmol) wassuspended in 1M aq. NaOH (40 mL) and the mixture was stirred at 60° C.overnight. The reaction mixture was cooled to rt and washed withhexanes. The aqueous layer was then separated and acidified with 6N HClto pH 2. A white precipitate was collected washed with water and driedto give 4-ethyl-2-methoxybenzoic acid (1.8 g, 97%) as a white solid. ¹HNMR (300 MHz, dMSO): δ 1.16-1.20 (t, 3H), 2.60-2.65 (dd, 2H), 3.80 (s,3H), 6.82-6.84 (d, 1H), 6.95 (s, 1H), 7.57-7.59 (d, 1H).

Example 18c Methyl 4-ethyl-2-methoxybenzoate

To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inertatmosphere Iron (III) acetylacetonate (398 mg, 1.17 mmol) giving a redcolor. Then EtMgBr (29 ml of 1M solution in ether) was added dropwiseunder vigorous stirring. The mixture turned dark brown and then violetand then was stirred for 15 more min. The reaction was diluted withether and quenched upon the addition of aq. HCl (1M, 50 mL). The crudeproduct was extracted with ether and the combined organic layers weresuccessively washed with water and brine, dried over MgSO₄, filtered andevaporated. The residue was purified on silica gel (Eluent: 30% EtOAc inhexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as anoil. ¹H NMR (300 MHz, dMSO): δ 1.20-1.22(t, 3H), 2.65-2.7 (dd, 2H), 3.9(s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H).

Example 18d Methyl 4-chloro-2-methoxybenzoate

A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH(18 mL) and conc. H₂SO₄ (1.5 mL) was refluxed overnight. MeOH wasevaporated and the residue was extracted to EtOAc and successivelywashed with water and brine, dried over MgSO₄, filtered and evaporatedto give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g,96%).

Additional “Triazole” compounds were synthesized (A1-22) or purchased(A23-26 from Asinex, Russia; A27 from Maybridge, England,—) wereexperimentally tested and found to have a relatively high level ofeffectiveness as an activator of a hT1R1/hT1R3 umami receptor expressedin an HEK293 cell line. The results of that testing are shown below inTable A.

TABLE A Triazoles Compound No. Compound Umami EC₅₀ (μM) Ec₅₀ ratio (vs.MSG) @ (μM) A1

0.17 2.19 0.01 A2

0.18 1.9 0.01 A3

0.24 2.01 0.3 A4

0.37 6.22 0.1 A5

0.42 1.5 0.03 A6

0.52 A7

0.74 2.33 0.03 A8

0.94 A9

1.07 A10

1.18 6.01 0.3 A11

1.35 A12

1.86 1.97 0.1 A13

2.12 7.36 0.3 A14

2.48 A15

2.54 2 0.1 A16

2.58 3.16 0.3 A17

2.89 3.02 0.3 A18

4.08 2.13 0.3 A19

6.49 2.01 0.3 A20

7.37 4.84 0.3 A21

9.41 A22

7.38 A23

12.95 A24

6.05 A25

13.06 A26

1.89 A27

7.92

Additional “pyridazine” compounds were purchased (B1-2 from Asinex ofMoscow, Russia; B3 from ICN biomedical research of Irvine, Calif.; B4from Life Chemicals of Burlington, Canada) and experimentally tested andfound to have good effectiveness as an activator of a hT1R1/hT1R3 umamireceptor expressed in an HEK293 cell line. The results of that testingare shown below in Table B.

TABLE B Pyridazines Compound No. Compound Umami EC₅₀ (μM) Ec₅₀ ratio(vs. MSG) @ (μM) B1

0.6 B2

1.7 B3

8.4 B4

3.61

Additionally a “tetrazole” compound purchased from Ryan Scientific ofIsle of Palms, S.C., was experimentally tested and found to have goodeffectiveness as an activator of a hT1R1/hT1R3 umami receptor expressedin an HEK293 cell line. The result of that testing is shown below inTable C.

TABLE C Tetrazole Compound No. Compound Umami EC₅₀ (μM) Ec₅₀ ratio (vs.MSG) @ (μM) C1

5.91Umami/Savory Flavor Experiments Using Human Panelists:

General Panelist Selection: Basic screening of sensory taste testers.Potential panelists were tested for their abilities to rank and rateintensities of solutions representing the five basic tastes. Panelistsranked and rated intensity of five different concentrations of each ofthe five following compounds: sucrose (sweet), sodium chloride (salty),citric acid (sour), caffeine (bitter), and monosodium glutamate(savory). In order to be selected for participation in testing,panelists needed to correctly rank and rate samples for intensity, witha reasonable number of errors.

Preliminary Taste Tests: The panelists selected in the above procedurewere deemed qualified for performing Preliminary Taste Testingprocedures. The preliminary taste tests are used to evaluate newcompounds for intensity of basic tastes and off-tastes. A small group ofpanelists (n=5) taste approximately 5 concentrations of the compound(range typically between 1-100 μM, in half-log cycles, e.g., 1, 3, 10,30, and 100 μM) in water and in a solution of 12 mM MSG to evaluateenhancement. Panelists rate the five basic tastes (sweet, salty, sour,bitter, and savory) as well as off-tastes (such as chemical, metallic,sulfur) on a labeled magnitude scale. Samples are served in 10 mLportions at room temperature. The purpose of the test is to determinethe highest concentration at which there is no objectionable off-taste,and determine if obvious savory taste or enhancement of savory tasteexists at any of the concentrations tested.

If the compound is effective and does not have objectionable off-tastes,it is tested with a trained (expert panel) in a larger study.

Trained Panelist Selection: A trained expert panel was used to furtherevaluate compounds that had been tested with the preliminary taste test.

Panelists for the trained panel were selected from the larger group ofqualifying taste panelists. Panelists were further trained on savorytaste by ranking and rating experiments using MSG and IMP combinations.Panelists completed a series of ranking, rating, and difference fromreference tests with savory solutions. In ranking and ratingexperiments, panelists evaluated easy MSG concentrations (0, 6, 18, 36mM) and more difficult MSG concentrations (3, 6, 12, 18 mM MSG) inwater.

Compound Testing with Trained Panel: Compounds tested by the trainedpanel were evaluated in difference from reference experiments. Panelistswere given a reference sample (12 mM MSG+100 μM IMP) and asked to ratesamples on a scale of −5 to +5 in terms of difference in savory tastefrom the reference (score: −5=much less savory taste than the reference;0=same savory taste as the reference; +5=much more savory taste than thereference). Test samples were solutions with varying amounts of MSG,IMP, and the compound. Typically, each session compares the referencesample to numerous test samples. Tests typically included varioussamples with varying concentrations of MSG and IMP, as well as one blindsample of the reference itself, to evaluate panel accuracy. Results ofthe taste tests are describe in table 3 and shows that compounds of theinvention have been found to provide savory taste or enhancement of thesavory taste at 1 uM+MSG when compared to 100 μM IMP+MSG. Compounds weretested against the reference in samples with and without 12 mM MSG. Allsamples were presented in 10 ml volumes at room temperature. Twosessions were completed for each compound tested to evaluate panelreproducibility.

Taste Test in Product Prototype: could be done similarly as describedabove.

TABLE D Savory Taste Test Results Compound No. Chemical Name Taste DataExample 1 2-((5-(2-methoxy-4- 12 mM MSG + 1 μM cpd 1 as strong asmethylphenyl)-1H-1,2,4-triazol-3- 12 mM MSG + 100 μM IMPylthio)methyl)pyridine Example 1 2-((5-(2-methoxy-4- 1 μM cpd 1 (in theabsence of MSG) as methylphenyl)-1H-1,2,4-triazol-3- strong as 12 mM MSGylthio)methyl)pyridine Example 3 2-((5-(2,4-dimethylphenyl)-1H- 12 mMMSG + 0.3 μM cpd as strong as 1,2,4-triazol-3- 12 mM MSG + 100 μM IMPylthio)methyl)pyridine Example 4 2-((5-(4-Ethylphenyl)-1H-1,2,4- 12 mMMSG + 1 μM cpd as strong as triazol-3-ylthio)methyl)pyridine 12 mM MSG +100 μM IMP Example 4 2-((5-(4-Ethylphenyl)-1H-1,2,4- 1 μM cpd 4 (in theabsence of MSG) as triazol-3-ylthio)methyl)pyridine strong as 12 mM MSG

Example 19 Soup Preparation Using an Ethanol Stock Solution

A compound of the invention is diluted using 200 proof ethanol to 1000×the desired concentration in soup. The compound can be sonicated and/orheated to achieve complete solubility in ethanol. The soup is made byadding 6 g of vegetable bouillon base in 500 mL of hot water in a glassor stoneware bowl. The water is heated to 80° C. The concentration ofMSG in the dissolved bouillon is 2.2 g/L and no IMP added. After thebouillon base is dissolved, the ethanol stock solution is added to thesoup base. For 500 mL of soup, 0.5 mL of the 1000× ethanol stock isadded for a final ethanol concentration of 0.1%. If the ethanolinterferes with the taste of the soup, a higher concentration of ethanolstock solution can be prepared provided the compound is soluble.

Example 20 Chip Preparation

A comestibly acceptable carrier composition comprising a compound ofFormula (I) is made by mixing the compound of Formula (i) with a saltmixture (typically a mixture of sodium chloride and monosodiumglutamate) so that a 1.4% of the salt mixture added w/w to chips wouldresult in the desired concentration of MSG and the compound of Formula(I). For 1 ppm final of the compound on chips, 7 mg of the compound ismixed with 10 g of salt and/or MSG. The mixture is ground using a mortarand pestle until mixed well. The chips are broken into uniform smallpieces by using a blender. For each 98.6 g of chips, 1.4 g of the saltmixture is weighed out. The chip pieces are first heated in a microwavefor 50 seconds or until warm. The pieces are spread out on a large pieceof aluminum foil. The salt mixture is spread evenly over the chips. Thechips are then placed in a plastic bag making sure that all the salt isplace in the bag as well. The salt mixture and chips are then shaken toensure that the salt is spread evenly over the chips.

Example 21 Juice Preparation

A compound of Formula (I) is diluted using 200 proof ethanol to 1000times the desired concentration in a vegetable juice. The alcoholsolution of the compound is further blended with natural and/orartificial flavors (including MSG) to make a “key”. The flavor key isblended with a portion of vegetable juice concentrate to assurehomogeneity. The remainder of the juice concentrate is diluted withwater and mixed. Sweeteners, such as HFCS (High Fructose Corn Syrup),aspartame, or sucralose, can be mixed in and blended. Theflavor/compound portion is added as a final step, and blended.

Example 22 Spicy Tomato Juice or Bloody Mary Mix

A compound of Formula (I) is added as a dry ingredient to a spice blendthat may include MSG, and mixed thoroughly. Spice blend is dispersedinto a portion of the tomato paste, blended, and that blended paste isfurther blended into the remaining paste. The paste is then diluted withwater. It may be processed at high temperature for a short time.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof some of the embodiments of the invention being indicated by thefollowing claims.

We claim:
 1. A taste modified comestible food or beverage compositioncomprising: a) at least one comestible food or beverage composition, orone or more precursors thereof, and b) at least one compound having theformula:

wherein i) Ar is a monocyclic or bicyclic aryl or heteroaryl radicalcomprising one or two aromatic rings independently selected from benzenerings and five or six membered heteroaryl rings, each aromatic ringoptionally having one, two, or three R²⁰ substituent radicals boundthereto, wherein each R²⁰ radical is independently selected fromhydroxyl, NH₂, NO₂, SH, SO₃H, P(O)(OH)₂, halogen, or a C₁-C₄ organicradical; ii) hAr¹ is a five or six-membered heteroaryl ring radicalhaving from 1 to 4 heteroatoms independently selected from oxygen,sulfur and/or nitrogen, wherein any remaining members of theheteroaromatic ring are independently selected from CR⁶, N, NR⁷; iii) Xis O, S, S(O), SO₂, CR⁸R⁹, or NR¹⁰; iv) n is the integer zero, one, two,or three; v) R³, R⁴, R⁸ and R⁹ are independently selected from hydrogen,oxygen, hydroxyl, NH₂, SH, halogen, or a C₁-C₄ organic radical, and R⁷and R^(l0) are independently selected from hydrogen, hydroxyl, or aC₁-C₄ organic radical, and R⁶ is hydrogen, halogen, or a C₁-C₄ organicradical; vi) hAr² is a five or six-membered heteroaryl ring having atleast one ring carbon atom and at least one ring nitrogen atom, andwherein the remaining members of the heteroaryl ring are independentlyselected from CR³⁰, CH, N, NR³¹, O, and S, n″ is zero, one, or two,wherein each R³⁰ is independently selected from hydroxyl, NH₂, NO₂, SH,SO₃H, P(O)(OH)₂, a halogen, or a C₁-C₄ organic radical, and each R³¹ isindependently selected from hydrogen, or a C₁-C₄ organic radical; or acomestibly acceptable salt thereof; and the compound is present in aconcentration from about 0.01 ppm to about 30 ppm.
 2. The comestiblecomposition of claim 1 wherein the R²⁰ and R³⁰ radicals areindependently selected from the group consisting of hydroxy, SH, NH₂,halogen, alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN,CO₂H, CHO, COR²¹, CO₂R²¹, amide, NHR²¹, NR²¹R^(21′), SR²¹, S(O)R²¹, andSO₂R²¹, wherein R²¹ is an alkyl.
 3. The comestible composition of claim1 wherein the R²⁰ and R³⁰ radicals are independently selected from thegroup consisting of hydrogen, hydroxy, fluoro, chloro, NH₂, NHCH₃,N(CH₃)₂, CO₂CH₃, amide, SEt, SCH₃, methyl, ethyl, isopropyl,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxygroups.
 4. The comestible composition of claim 1 wherein Ar comprises abenzene ring.
 5. The comestible composition of claim 4 wherein the R²⁰radicals are independently selected from hydroxy, SH, NH₂, a halogen ora an alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H,CHO, COR²¹, CO₂R²¹, NHR²¹, NR²¹R^(21′), SR²¹, S(O)R²¹, and SO₂R²¹wherein R²¹ and R^(21′) are independently selected alkyls.
 6. Thecomestible composition of claim 1 wherein Ar has the structure:

wherein the R²⁰ and R^(20′) radicals are independently selected fromhydrogen, hydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, CN, SEt,SCH₃, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy groups.
 7. The comestible compositionof claim 1 wherein Ar has the structure:

wherein the R²⁰ and R^(20′) radicals are independently selected fromhydrogen, hydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt,SCH₃, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy groups.
 8. The comestible compositionof claim 1 wherein Ar has the structure:


9. The comestible composition of claim 1 wherein Ar comprises a pyridyl,pyrazinyl, pyridazinyl or pyrimidinyl ring.
 10. The comestiblecomposition of claim 9 wherein the R²⁰ substitutent radicals areindependently selected from hydrogen, hydroxy, fluoro, chloro, NH₂,NHCH₃, N(CH₃)₂, CO₂CH₃, CN, SEt, SCH₃, methyl, ethyl, isopropyl,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxygroups.
 11. The comestible composition of claim 1 wherein Ar comprises afuranyl, thiofuranyl, pyrrolyl, pyrazolyl, oxazolyl, or isoxazolyl ring.12. The comestible composition of claim 11 wherein the R²⁰ substitutentradicals are independently selected from hydrogen, hydroxy, fluoro,chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, SEt, SCH₃, methyl, ethyl,isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy groups.
 13. The comestible composition of claim 1wherein Ar comprises a benzofuranyl, benzothiofuranyl, or benzopyrrolylring.
 14. The comestible composition of claim 13 wherein the R²⁰ and R³⁰radicals are independently selected from the group consisting ofhydrogen, fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl,methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
 15. Thecomestible composition of claim 1 wherein hAr¹ comprises a pyridyl,pyrazinyl, pyridazine or pyrimidinyl ring having the structure:

wherein the R⁶ and R^(6′) radicals are independently present or absentand are independently selected from fluoro, chloro, methyl, ethyl,isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy groups.
 16. The comestible composition of claim 1wherein hAr¹ is a pyridyl, pyrazinyl, pyridazinyl, or pyrimidinylradical having the structure:


17. The comestible composition of claim 1 wherein hAr¹ has thestructure:

wherein R⁶ is hydrogen or a C₁-C₄ alkyl or alkoxyl radical, and R⁷ ishydrogen or a C₁ -C₄ alkyl radical.
 18. The comestible composition ofclaim 17 wherein R⁶ and R⁷ are hydrogen.
 19. The comestible compositionof claim 1 wherein hAr¹ has the structure:

wherein R⁷ is hydrogen or a C₁-C₄ organic radical.
 20. The comestiblecomposition of claim 19 wherein R⁷ is hydrogen.
 21. The comestiblecomposition of claim 1 wherein hAr¹ has the structure

wherein R⁷ is hydrogen or a C₁-C₄ alkyl radical.
 22. The comestiblecomposition of claim 1 wherein hAr¹ has the structure:


23. The comestible composition of claim 1 wherein hAr¹ has thestructure:


24. The comestible composition of claim 1 wherein hAr¹ has thestructure:


25. The comestible composition of claim 1 wherein n is one or two. 26.The comestible composition of claim 1 wherein n is one.
 27. Thecomestible composition of claim 1 wherein X is S, NH, or O.
 28. Thecomestible composition of claim 1 wherein X is S.
 29. The comestiblecomposition of claim 1 wherein R³ and R⁴ are hydrogen.
 30. Thecomestible composition of claim 1 wherein R⁷ and R¹⁰ are hydrogen. 31.The comestible composition of claim 1 wherein R⁶, R⁸, and R⁹ arehydrogen.
 32. The comestible composition of claim 1 wherein R³, R⁴, R⁶,R⁷, R⁸, R⁹, and R¹⁰ are hydrogen.
 33. The comestible composition ofclaim 1 wherein hAr² comprises a pyridyl, pyrazinyl, or pyrimidinylring.
 34. The comestible composition of claim 1 wherein hAr² has thestructure:

wherein n″ is an integer selected from 0, 1, or 2, and each R³⁰ isindependently selected from the group consisting of hydroxy, fluoro,chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, amide, CN, SEt, SCH₃, methyl,ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy.
 35. The comestible composition of claim 1 wherein thepyridine radical is a 2-pyridine radical having the structure:

wherein n″ is an integer selected from 0, 1, or 2, and each R³⁰ isindependently selected from the group consisting of hydroxy, fluoro,chloro, NH₂, NHCH₃, N(CH₃)₂, CO₂CH₃, amide, CN, SEt, SCH₃, methyl,ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy.
 36. The comestible composition of claim 35 wherein n″is
 0. 37. The comestible composition of claim 35 wherein n″ is
 1. 38.The comestible composition of claim 1 wherein further comprising atleast a savory flavor modulating amount of monosodium glutamate.
 39. Thecomestible composition of claim 1 wherein the log¹⁰ of the partitioncoefficient of the compound between n-octanol and water is less than5.5.
 40. The comestible composition of claim 1 that is a food for animalconsumption.
 41. The comestible composition of claim 1 that is a foodfor human consumption.
 42. The comestible composition of each of claims1, 6, 19, 32, or 34 that is selected from the group consisting ofconfectioneries, bakery products, ice creams, dairy products, sweet orsavory snacks, snack bars, meal replacement products, ready meals,soups, pastas, noodles, canned foods, frozen foods, dried foods, chilledfoods, oils and fats, baby foods, and spreads.
 43. The comestiblecomposition of each of claims 1, 6, 19, 32, or 34 that comprises one ormore meats, poultry, fish, vegetables, grains, or fruits.
 44. Thecomestible composition of each of claims 1, 6, 19, 32, or 34 that is afrozen food, an uncooked food, or a fully or partially cooked food. 45.The comestible composition of each of claims 1, 6, 19, 32, or 34 that isa soup, a dehydrated or concentrated soup, or a dry soup.
 46. Thecomestible composition of each of claims 1, 6, 19, 32, or 34 that is asnack food.
 47. The comestible composition any of claim 1, 6, 19, 32, or34 that is a cooking aid product, a meal solution product, a mealenhancement product, a seasoning, or a seasoning blend.
 48. Thecomestible composition of each of claims 1, 6, 19, 32, or 34 that is abeverage, a beverage mix, or a beverage concentrate.
 49. The comestiblecomposition of each of claims 1, 6, 19, 32, or 34 that is a soda, orjuice.
 50. The comestible composition of each of claims 1, 6, 19, 32, or34 that is an alcoholic beverage.
 51. The comestible composition ofclaim 1 wherein the compound is present in a concentration from about0.05 ppm to about 15 ppm.
 52. The comestible composition of claim 1wherein the compound is present in a concentration from about 0.1 ppm toabout 3 ppm.
 53. A savory flavor modified food or beverage productcomprising: a) at least one food or beverage product, or one or moreprecursors thereof, and b) at least about 0.01 ppm of one or moretriazole compound having the Formula (IB):

or a comestibly acceptable salt thereof, wherein i) n′ is zero, one,two, or three, and each R²⁰ is independently selected from hydroxy, SH,NH₂, a halogen, and a C₁-C₄ radical selected from an alkyl, alkoxyl,alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR²¹, CO₂R²¹,NHR²¹,NR²¹R^(21′), or SR²¹radical, wherein R²¹ and R^(21′) areindependently selected alkyls, ii) n″ is zero, one, or two, and eachR³⁰is independently selected from hydroxy, SH, NH₂, a halogen, and aC₁-C₄ radical selected from an alkyl, alkoxyl, alkoxy-alkyl,hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR³², CO₂R³², amide, NHR³²,NHR³²R^(32′), or SR³² radical, wherein R³² and R^(32′) are independentlyselected alkyls, iii) X is NH, O, S, S(O), SO₂, or CH₂, iv) Ar is aphenyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, thiofuranyl, orpyrrolyl ring.
 54. The modified food or beverage product of claim 53wherein the triazole compound is present in the modified comestibleproduct at a concentration from about 0.01 ppm to about 40 ppm.
 55. Acompound having the Formula (IB):

or a comestibly acceptable salt thereof, wherein i) n′ is zero, one,two, or three, and each R²⁰ is independently selected from hydroxy, SH,NH₂, a halogen, and a C₁-C₄ radical selected from an alkyl, alkoxyl,alkoxy-alkyl, hydroxyalkyl, haloalkyl, CN, CO₂H, CHO, COR²¹, CO₂R²¹,NHR²¹, NR²¹R^(21′), or SR²¹ radical, wherein R²¹ and R^(21′) areindependently selected alkyls, ii) n″ is zero, one, or two, and each R³⁰is independently selected from hydroxy, SH, NH₂, a halogen, and a C₁-C₄radical selected from an alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl,haloalkyl, CN, CO₂H, CHO, COR³², CO₂R³², amide, NHR³², NHR³²R^(32′), orSR³² radical, wherein R³² and R³² are independently selected alkyls,iii) X is NH, O, S, S(O), SO₂, or CH₂, and iv) Ar is a phenyl, pyridyl,pyrazinyl, pyrimidinyl, furanyl, thiofuranyl, or pyrrolyl ring.
 56. Thecompound of claim 55, which is selected from the group consisting of:2-((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-ylthio)methyl)pyridine;2-((5-(2-methoxy-4-methylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine;2-((5-(2,4-dimethylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine;2-((5-(4-Ethylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine;2-((5-(4,5-dimethylfuran-2-yl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine;2-((5-(4-Ethyl-2-methylphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine;and2-((5-(4-ethyl-2-methoxyphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine;or a comestibly acceptable salt thereof.
 57. The compound of claim 55,wherein X is S.
 58. The compound of claim 55, wherein Ar is phenyl. 59.The compound of claim 55, wherein n′ is zero, one, two, or three; and n″is zero.
 60. The compound of claim 55, wherein X is S; Ar is phenyl; n′is zero, one, two, or three; and n″ is zero.